Table of contents :

Viruses

• dsDNA viruses, no RNA stage
• Adenoviridae : the adenoviruses: a family of DNA viruses having a nonenveloped icosahedral virion 80–110 nm in diameter with 252 capsomers. The genome consists of a single linear molecule of dsDNA (MW 20–30 x 10⁶, size 36–38 kbp). Viruses contain at least 10 structural proteins and are ether-resistant and acid-stable; some are heat-sensitive. Replication occurs in the nucleus and structural proteins are synthesized in the cytoplasm; assembly occurs in the nucleus and virions are released by cell destruction. Host range is generally narrow and transmission may be direct or indirect. Genera include :
• Aviadenovirus : adenoviruses of birds; a genus of viruses of the family Adenoviridae that infect many bird species, causing a wide variety of diseases; infection by some viral species is asymptomatic. Species names are abbreviated by a prefix derived from the host genus and a number designating the serotype, e.g., DAdV-2 for duck adenovirus 2.
• Mastadenovirus : mammalian adenoviruses; a genus of viruses of the family Adenoviridae that infect mammals, causing disease of the respiratory tract, gastrointestinal tract, conjunctiva, central nervous system, and urinary tract; infection may be asymptomatic. Many species induce malignancy. Human viruses are grouped into 7 subgenera (A–G) on the basis of structural, immunological, biological, and chemical characteristics :
• Human adenovirus serotype A
• Human adenovirus type 12

=> CNS infections in immunocompromised hosts
=> croup
Induces tumor in hamster babies.
• Human adenovirus type 18
• Human adenovirus type 31
=> febrile respiratory infection and diarrhoea
• Human adenovirus serotype B
• Human adenovirus type 3 / pharyngoconjunctival fever virus
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever (PCF)
=> epidemics of aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia
• Human adenovirus type 7
• Human adenovirus type 7a
=> pharyngoconjunctival fever (PCF)
=> epidemics of aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia ("recruit fever")
=> morbilliform maculopapular exanthema
=> CNS infections in immunocompromised hosts
Induces tumor in hamster babies.
• Human adenovirus type 7d
• Human adenovirus type 11
• Human adenovirus type 11 (Ad11A) (strain BC34)
• Human adenovirus type 11 (Ad11P) (strain Slobiski)
=> acute hemorrhagic cystitis in babies
=> acute hemorrhagic conjunctivitis
• Human adenovirus type 14
=> pharyngoconjunctival fever
=> epidemics of acute bronchitis or interstitial pneumonia ("recruit fever")
• Human adenovirus type 16

Induces tumor in hamster babies.
• Human adenovirus type 21
=> epidemics of aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia ("recruit fever")
=> acute hemorrhagic cystitis in babies
• Human adenovirus type 34
• Human adenovirus type 34a
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
• Human adenovirus type 35
• Human adenovirus type 35p
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
• Human adenovirus type 50
=> often-fatal illnesses in immunocompromised individuals, including bone marrow transplant recipients and cancer and AIDS patients
• Human adenovirus serotype C
• Human adenovirus type 1
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever
• Human adenovirus type 2
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever (?)
=> febrile respiratory infection and diarrhoea
• Human adenovirus type 5
Proteomics : it up-regulates c-PI31, which delays immunoproteasome formation hence affecting presentation of the immunoproteasome-dependent epitope E1B. E1A interacts with the 19S S4 ATPase subunit of the 26S proteasome.
=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
=> morbilliform maculopapular exanthema
=> pharyngoconjunctival fever
• Human adenovirus type 6

=> pharyngoconjunctival fever
=> pertussis-like syndrome : a syndrome clinically indistinguishable from pertussis but in which there is no evidence of infection with Bordetella pertussis or Bordetella parapertussis, although evidence of other infectious agents, such as adenoviruses types 1, 2, 3, 5, and 6, can be demonstrated
• Human adenovirus serotype D
• Human adenovirus type 8 / epidemic keratoconjunctivitis virus
=> epidemic keratoconjunctivitis (EKC)
• Human adenovirus type 9
• Human adenovirus type 10
• Human adenovirus type 13
• Human adenovirus type 15
• Human adenovirus type 17
• Human adenovirus type 19
=> epidemic keratoconjunctivitis (EKC)
• Human adenovirus type 19a
• Human adenovirus type 19p
• Human adenovirus type 20
• Human adenovirus type 22
• Human adenovirus type 23
• Human adenovirus type 24
• Human adenovirus type 25
• Human adenovirus type 26
• Human adenovirus type 27
• Human adenovirus type 28
• Human adenovirus type 29
• Human adenovirus type 30
• Human adenovirus type 32

=> CNS infections in immunocompromised hosts
• Human adenovirus type 33
• Human adenovirus type 36
=> obesity (RR = 5-6)
• Human adenovirus type 37
=> epidemic keratoconjunctivitis (EKC)
• Human adenovirus type 38
• Human adenovirus type 39

=> interstitial pneumonia with dissemination or urinary tract infections (UTI) in immunocompromised hosts
• Human adenovirus type 42
• Human adenovirus type 43
• Human adenovirus type 44
• Human adenovirus type 45
• Human adenovirus type 46
• Human adenovirus type 47
• Human adenovirus type 48
• Human adenovirus serotype E
• Human adenovirus type 4
• Human adenovirus type 4a
=> epidemic aspecific acute pharyngitis, acute bronchitis or interstitial pneumonia ("recruit fever")
• Human adenovirus serotype F
• Human adenovirus type 40
• Human adenovirus type 41
=> acute gastroenteritis after 24-72 hours incubation => cholangiohepatitis occurs in immunocompromised hosts as a result of ascending infection from the gastrointestinal tract to the biliary tree.

• titi monkey adenovirus (TMAdV) : the scientist who fell ill had been in close contact with Titi monkeys of a colony at the California National Primate Research Center in Davis of 55 monkeys housed at the center, 23 (about 40%) became seriously ill with upper respiratory symptoms that progressed to pneumonia and an inflammation of the liver. A total of 19 monkeys, or about 83% of those infected, died . Though she became seriously ill with pneumonia around the same time the monkeys were falling ill, she was not hospitalized and recovered after about 4 weeks. Her blood tested positive for antibodies to the virus 3 months after the epidemic^{ref1, ref2}
  
Epidemiology : outbreaks of adenovirus infection are not uncommon in military establishments, and some types of adenovirus infection have been associated with conjunctivitis in the past. In Feb 2004 following an outbreak of conjunctivitis affecting about 230 soldiers in 6 barracks in northern and southern Hessen, some 4700 members of the 14000 troops stationed in Hesse by the German Federal Armed Forces have have been withdrawn from service. The bases at Schwalmstadt (where the epidemic began), Schwarzenborn, Stadtallendorf, and Neustadt will be closed for 3 weeks while the premises are disinfected
• Japan : prior to 1995, most isolates were (in descending order) adenovirus types 3, 2 and 1. In 1997, most were types 2, 3 and 7. In 1999, most were types 2, 3 and 1. Adenovirus type 7 infection rates peak during May to September, with 55 percent of patients in the age group 0 to 4 years. An nationwide outbreak of Adenovirus 7 infection (75 cases) was reported in 1995. During 1991 to 2003, laboratory reports ranged from 1200 to 3000 per year.
• 17 032 isolates were recovered during 1982 to 1993 (includes 1080 in 1993): 6722 respiratory, 3428 eye and 1605 gastrointestinal.
• 10 010 isolates were recovered during 1995 to 1999: 7207 respiratory, 1321 eye and 1677 gastrointestinal.
• reports for 2003 included 886 isolates of adenovirus type 3; and 1421 respiratory, 84 eye and 269 gastrointestinal isolates.
Reports of pharyngoconjunctival fever ranged from 6249 (in 1997) to 15 812 (in 1991).
•  these data represent cases reported by general physicians, internists and ophthalmologists.
•  40,714 cases of pharyngoconjunctival fever were reported by pediatric sentinel clinics in 2003.
Notable outbreaks:
• 1973 : an outbreak (28 cases) of adenovirus 8 epidemic keratoconjunctivitis was reported at a babies' home in Sapporo.
• 1990 (publication year) : an outbreak (14 cases) of adenovirus 37 keratoconjunctivitis was reported in an ophthalmology clinic in Yokohama.
• 1996 to 1997 : an outbreak (14 cases) of severe adenovirus 7 infection was reported on a pediatric ward in Hokkaido.
Proteomics :
• serotypes A, C, D, E and F all use :
• primary receptor : Coxsackievirus B and Adenovirus receptor (CAR / CVADR / CXADR), which interacts with the head domain of the adenoviral fiber protein, also called fiber knob. CAR is almost ubiquitously expressed (expecially in hepatocytes). Adjacent epithelium cells maintain cell contacts through homotypic interactions of the CAR protein, an immunoglobulin superfamily member that also serves as the receptor for adenoviruses. However, CAR exhibits polarized basolateral expression and might block virus escape to the apical surfaces when viral progeny are shed on basolateral surfaces. But adenoviruses express the protein fiber, which competitively inhibits CAR-CAR interactions, disrupting epithelial integrity. Thus, fiber is an adenovirus virulence factor that promotes viral dissemination. After the initial binding step, the viral particle achieves endocytotic internalization via interaction with ...
• secondary receptors : a_vb₃ , a_vb₅ (and a_vb₁?) integrins, which interact with the penton base. Integrin a_M mediates attachment but not internalization of adenovirus virions in monocytes, while integrin a_V also mediates internalization via clathrin-dependent endocytosis in both monocytes and epithelial cells.
• serotype B uses CD46 / MCP as receptor
Adenovirus internalized by alveolar macrophages is degraded with a half-life of 6 h while in epithelial cells < 5% is degraded by 48 h.
Genomics : it integrates into adenovirus/SV40 integration site 1 (ASVS1)
• E1B19K is a Bcl-2 ortholog.
They persist in lymphoid tissues, rhinopharynx, bowel and kidney (excreted in urines during pregnancy).
=> clinical manifestations : adenovirus infections are usually asymptomatic, but may be associated with diseases of the respiratory, ocular and gastrointestinal tract (types 40 and 41). It has been estimated that adenoviruses are responsible for 5-10% of paediatric respiratory infections (predominantly pharyngoconjunctival fever (PCF)). Respiratory infections in children are short-lived and rarely life-threatening. Outbreaks of adenovirus respiratory infections have been common among military recruits (mainly types 4, 7, 14 and 21), where rates of hospitalisation have reached 20%. As a result vaccines were developed against adenovirus types 3, 4, 7  and 21, but later withdrawn. Most outbreaks of pharyngoconjunctivital fever in school-age children have occurred occur during the summer, whereas the outbreaks among military recruits have occurred during winter, probably reflecting a different mode of transmission. Adenovirus types 8, 9 and 11 have been associated with outbreaks of keratoconjunctivitis (also known as shipyard eye) in adults. However, whereas multiple serotypes from different species have been described as causing cases or limited, irregular outbreaks of ocular disease in humans, there are only a few serotypes that regularly cause larger outbreaks or epidemics. The 2 types of ocular disease that are commonly caused by adenoviruses are pharyngoconjunctival fever (PCF) and epidemic keratoconjunctivitis (EKC). An interesting observation is that the 3 serotypes that cause EKC (Ad8, Ad19, and Ad37) use a cellular receptor (sialic acid) that is different from the cellular receptors used by other adenoviruses (CAR or CD46)
Laboratory examinations : basophilic Cowdry type B inclusion bodies
Therapy : at present, there are no licensed antivirals available to any of the adenoviruses. Cidofovir intravenously at 5 mg/kg weekly for 2 consecutive weeks, then every 2 weeks until 3 consecutive ADV-negative samples were documented from all previously invoved sites is safe and effective in pediatric HSCT recipients^ref
Prevention : an adenovirus type 4 vaccine and a triple type 4, 7 and 21 vaccine were employed with some degree of success in the USA. However, these vaccines are no longer in production, and there is some evidence that outbreaks of adenovirus-associated illness affecting military recruits are on the increase.
Used as transfection vector.
• Herpesviridae : the herpesviruses: a family of DNA viruses having a virion 102–200 nm in diameter consisting of four components: a lipid bilayer envelope with surface projections, a tegument of amorphous material, an icosahedral nucleocapsid with 162 prismatic capsomers, and a protein spool on which the DNA is wrapped. The genome consists of a single molecule of linear double-stranded DNA (MW 70–150 x 10⁶, size 124–235 kbp). Viruses contain at least 20 structural polypeptides and are sensitive to lipid solvents, heat, and extremes of pH. Replication occurs in the nucleus and the envelope is acquired by budding through the inner lamella of the nuclear membrane; virions are released by transport via the endoplasmic reticulum to the cell membrane. Persistence for the lifetime of the host is common and some herpesviruses induce neoplasia. Except cercopithecine herpes virus 1 and pseudorabies virus, all human herpesviridae are species-restricted. There are 3 subfamilies :
• Alphaherpesvirinae
• Simplexvirus
• cercopithecine herpes virus 1 / monkey B-virus / herpesvirus simiae / herpes virus B
Epidemiology : secondary transmission after a lab accident^{ref1, ref2}. In Jan 2005 4 Formosan rock monkeys (Macaca cyclopis) out of 27 in a wildlife shelter in Nantou County were put down after they were diagnosed as carriers
Genomics : there is evidence of distinct genotypes, and that isolates from different species of macaques vary in their pathogenicity for humans.
Transmission : the natural host is Asiatic macaque monkey, but, when reactivated, can be transmitted to humans usually via injury (bites and scratches), through handling infected monkey tissues, and more rarely by other routes such as the eye. B virus infection of humans is mainly restricted to animal handlers and pet owners, but there is a low risk in any contact with macaques
=> the incubation period in humans can be as short as 2 days, but several weeks is more common. Minor symptoms are followed quickly by severe ascending myelopathy, acute meningoencephalitis, and death
=> in 1997 mucocutaneous infection without injury was reported.
Prevention : if bitten or scratched, people should thoroughly cleanse their wounds with water and receive an immunoglobulin shot.
Prognosis : the death rate can be as high as 79%, and recovered patients may have neurologic impairment. However, the use of the antivirals acyclovir or gancyclovir can halt disease progression and assist recovery. Rapid diagnosis is essential
• human herpesvirus 1 (HHV-1) / herpes simplex virus 1 (HSV-1) / herpesvirus hominis 1 (HVH1)
Proteomics :
• glycoprotein B (gB) : HSV-8p is an immunodominant peptide
• glycoprotein D (gD) binds to herpesvirus entry mediator (HVEM) / herpesvirus entry protein A (HveA) / TR2 / LIGHTR : the BTLA binding site on HVEM overlaps with the binding site for the gD, but is distinct from where LIGHT binds, yet glycoprotein D inhibits the binding of both ligands, potentially nullifying the pathway^ref. Coreceptors : herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 / CD155 and herpesvirus entry protein C (HveC) / poliovirus receptor-related 1 (PVRL1) / nectin-1 / herpesvirus Ig-like receptor (HIgR) (that confined with E-cadherin to adherens junctions in epithelial cells is not very accessible to virus, whereas dissociation of cell junctions releases nectin-1 to serve more efficiently as an entry receptor)
• herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 (expressed in some human neuronal cell lines, fibroblastic cells, keratinocytes, and primary activated T lymphocytes) mediates the entry of 3 mutant HSV-1 strains (HSV-1(KOS)Rid1 ) that cannot use HVEM as co-receptor, but not wild-type HSV-1 strains
• ICP47 inhibits TAP.
• g34.5 dephosphorylates eIF2a and inhibits the shutoff of protein synthesis in metabolically-stressed host cells
• latency-associated transcript (LAT) is the only viral gene expressed during latent infection in neurons. LAT inhibits apoptosis and maintains latency by promoting the survival of infected neurons. No protein product has been attributed to the LAT gene and the mechanism by which LAT protects cells from apoptosis is not yet known. A miRNA encoded by the HSV-1 LAT gene confers resistance to apoptosis. Neuroblastoma cells transfected with a fragment of the LAT gene show reduced susceptibility to cell death. The anti-apoptotic function of LAT has been mapped to a region within the first exon. miR-LAT is generated from the exon 1 region of the HSV-1 LAT gene. The LAT miRNA accumulates in cells transiently transfected with the LAT gene fragment or infected with a wild-type strain of HSV-1. A mutant virus in which a 372-nucleotide fragment encompassing the mature miRNA was deleted neither protected the infected cells from apoptosis nor generated an miRNA. miR-LAT exerts its anti-apoptotic effect by downregulation of TGF-b₁ and SMAD3 expression, both of which are functionally linked in the TGF- pathway. The miRNA encoded by the HSV-1 LAT gene regulates the induction of apoptosis in infected cells by modulation of TGF- signalling and thus contributes to the persistence of HSV in a latent form in sensory neurons^ref
Transmission : oro-oral route
Pathogenesis : antibody-dependent enhancement (ADE) of viral infection. HSV-1 reduces CD1d surface expression on APCs. HSV-1 did not inhibit CD1d protein synthesis or enhance constitutive CD1d endocytosis. Instead, HSV-1 prevented the reappearance of endocytosed CD1d on the cell surface by redistributing endocytosed CD1d to the lysosome limiting membrane. HSV-1 might also inhibit the transport of newly synthesized CD1d to the cell surface. Such inhibition of CD1d surface expression impaired APC–mediated stimulation of NKT cells, supporting the idea that this mechanism may be an important HSV-1 immune evasion strategy^ref.
=> 95% of herpes up the waist and 40% of herpes down the waist
• at 1^st infection (early childhood) : after 2-12 days incubation
• herpetic gingival stomatitis (HGS) and oropharyngitis in babies before age 3 (the most common kind of primary infection) => eschar (=> squamous lip carcinoma), self-limiting within 10-14 days.
• herpetic fever : primary infection with HSV, with diffuse involvement of mucous membranes of the mouth and lips and the surrounding skin; fever and sometimes chills occur.
• recurrent herpes simplex labialis (HSL) / fever blisters / cold sores (prevalence : 20-40% of the US population) : in a normal person, the blister is gone 3-4 days after it appears. In an immunocompromised host, reactivation usually causes chronic ulcers that erode and spread. The lower lip is more commonly affected than the upper lip.
• eczema herpeticum (a kind of Kaposi's varicelliform eruption (KVE)) in individuals who have active or quiescent atopic dermatitis (AD).
• herpes gladiatorum / rugby player herpes / scrum-pox : HHV-1 infections are not uncommon among wrestlers, rugby players and others engaged in contact sports, with no single strain responsible for outbreaks^ref. In the case of wrestlers the condition is known as herpes gladiatorum (HG). Anderson^ref concluded from an analysis of the epidemiology and clinical analysis of several outbreaks of herpes gladiatorum that the National Federation of State High School Associations (NFHS) guidelines were inadequate to prevent and control outbreaks of HG. The focus of preventive efforts needed to change from mat cleanliness to more rapid detection of outbreaks by requiring culture results and appropriate therapy for all suspected bacterial and herpes lesions before allowing return to contact. To minimize and control spread of HG, treatment and isolation should be implemented based not only on vesicle formation but also on systemic signs and symptoms. Anderson (Jpn J Infect Dis. 2006 Feb;59(1):6-9, Feb 2006) has described subsequently the prophylactic use of valacyclovir (an inhibitory nucleoside analogue prodrug) to prevent outbreaks of primary herpes gladiatorum at a 28-day wrestling camp. The study evaluated the usage of valacyclovir to prevent acquisition of primary HG, due to human herpesvirus type 1, in high school wrestlers at a 28-day wrestling camp. At the beginning and end of camp, IgM and IgG anti-HSV-1 antibodies were collected. Out of 332 male wrestlers, aged 13-20, who entered camp, 94 elected to participate in blood sampling. 64 were on antiviral medication. Among the 94 wrestlers, 28 (29.8%) had positive IgG anti-HHV-1 titers. Of this group, 66 of 94, were human HHV-1 IgG seronegative. At the end of camp, 55 of these original seronegative individuals elected to participate in blood sampling and none had detectable IgM anti-human herpesvirus 1 or 2 antibodies. Compared to previous years without antiviral usage, introducing prophylactic valacyclovir reduced clinical HG outbreaks by 87% at this 28-day wrestling camp. Due to the high prevalence of this virus in high school wrestlers, Anderson recommended that serological testing should be done at the beginning of each season. HSV-1 seropositive individuals should consider being on antiviral medication throughout the season to minimize the risk of transmitting the virus to other wrestlers.
• herpetic whitlow (pustules on the finger or hand due to bacterial superinfection, often seen in health cares workers (dentists, ..) who have a tendency to touch HSV lesions without dressing gloves)
• proctitis
• non-gonococcal urethritis (NGUs)
• temporal lobe encephalitis in adults => epilepsy
• Alzheimer's disease (?)
• ocular herpes : herpetic stromal keratitis (HSK) (type II hypersensitivity mediated by T_h1 effector cells) leading to scarring, opacity, and blindness, and it is an important problem in common corneal surgeries or acute monolateral follicular conjunctivitis. In the preclinical phase, when HSV-1 replicates in the corneal epithelium, neutrophils invade the underlying corneal stroma. This transient response, triggered by replicating virus, is thought to control HSV replication and limit viral spread into peripheral tissues. During the clinical phase, a second wave of inflammatory cells, predominantly consisting of neutrophils, infiltrates the corneal stroma and destroy it. Paradoxically, virus antigens are largely focused in the epithelial layer of the cornea and not in the stromal layer, and viral antigens are eliminated before stromal inflammation develops. It is not clear what drives inflammation, whether viral antigens are necessary, or how viral antigens reach the stroma. It has been proposed that HSV travels from the corneal epithelium to sensory ganglia then returns to the stroma to cause disease. However, there is also evidence of HSV DNA and infectious virus persistent in corneas, and HSV can be transmitted to transplant recipients. US9^- HSV mutant, that had diminished capacity to move in neuronal axons, replicated and spread normally in the mouse corneal epithelium and to the trigeminal ganglia. However, US9^- HSV was unable to return from ganglia to the cornea and failed to cause periocular skin disease, which requires zosteriform spread from neurons. Nevertheless, US9- HSV caused keratitis. Therefore, herpes keratitis can occur without anterograde transport from ganglia to the cornea, probably mediated by virus persistent in the cornea^ref.
• disseminated infection in immunocompromised individuals (herpes esophagitis, interstitial pneumonia : lethality 50%)
• at reactivations : papules => vesicles
• Behçet-Adamantes-Gilberto syndrome (?)
• type IA insulin-dependent diabetes mellitus (?)
Laboratory examinations : Cowdry type A inclusion bodies (Lipschutz inclusions), owl-eye inclusions
Experimental animal models : Callithrix jacchus is more susceptible to HSV-1 encephalitis than Aotus trivirgatus (expensive, difficult to obtain and to maintain in captivity)
Used as transfection vector.
Therapy : acyclovir; alcoholic povidone-iodine^ref
• human herpesvirus 2 (HHV-2) / herpes simplex virus (HSV-2)
Proteomics : glycoprotein D (gD) binds to herpesvirus entry mediator (HVEM) / TR2 / LIGHTR. Coreceptors : herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 / CD155 and herpesvirus entry protein C (HveC) / poliovirus receptor-related 1 (PVRL1) / nectin-1 / herpesvirus Ig-like receptor (HIgR)
=> 5% of herpes up the waist and 60% of herpes down the waist (genital herpes) (sexual route). About 25-30% of people age 18-29 years are seropositive for HSV-2 (2/3 of those do not know they have it because many primary infections are often asymptomatic.  The worst primary disease occurs in people who are seronegative for HSV-1.
• at 1^st infection (early childhood) : after 2-12 days incubation
• genital herpes / herpes genitalis or progenitalis (painful lesions) : cervicitis, vulvovaginitis, balanoposthitis, non-gonococcal urethritis (NGUs), proctitis (severe in male homosexuals). The lesions are very superficial (unlike chancroid or syphilis, whose lesions are lumpy). The primary lesions stay for 2-3 weeks, but recurrent usually heal within 3-5 days.
• neonatal herpes (perinatal contagion) => dissemination, encephalitis, and visceral disease (interstitial pneumonia, hepatic necrosis). If the mother has been seropositive for some time before the birth, then transplacental IgG serve as a protective mechanism for the newborn. >50% mortality.
• eczema herpeticum / Kaposi's varicella-like eruption in babies with atopic dermatitis, seborrhoic dermatitis,pemphigus or Wiskott-Aldrich syndrome => generalized herpes (including erythema multiforme, herpetic stromal keratitis (HSK), retinal necrosis)
• Bell’s palsy
• encephalitis when the virus travels up the nerve to the brain instead of down towards the lip (lethality 50%)
• lymphocytic meningitis follows primary genital herpes in 10% of patients. Meningitis may be recurrent in about 30% of patients (recurrent lymphocytic meningitis (RLM) / Mollaret’s meningitis) :. HLA-DRB1*01 and -B*27 alleles and low plasma IgG1 levels may be significant risk factors for RLM^ref
• gingivostomatitis and acute pharyngitis in adults following oro-genital contacts => eschar (=> squamous lip carcinoma)
• cervical squamous cell carcinoma (priming effect for HPV-6, HPV-10, HPV-11, HPV-16, and HPV-18 ?)
It undergoes latency in lumbar and sacral ganglia thanks to latency-associated transcripts (LAT).
• at reactivations it is milder
Laboratory examinations : owl-eye inclusions,Cowdry type A inclusion bodies (Lipschutz inclusions).
Used as transfection vector.
Therapy : acyclovir
Diagnosis : multinucleated giant cells are seen (Tzanck cells)
Chemotherapy : PO  or topic acyclovir or cidofovir (if resistance occurs => foscarnet), idoxuridine, vidarabine and trifluridine.
• Varicellovirus
Proteomics : UL49.5 protein, an interaction partner for glycoprotein M, inactivates TAP via inhibition of peptide transport through a conformational arrest of the transporter and degradation of TAP by proteasomes. UL49.5 is degraded along with TAP via a reaction that requires the cytoplasmic tail of UL49.5^ref
• Human herpesvirus 3 / varicella-zoster virus (HHV-3 / VZV)
Epidemiology :
• USA : chickenpox-related deaths happened in about 100 people a year before 1995, prior to introduction of an improved vaccine. The CDC states that about 40 percent of deaths due to chickenpox happen in children younger than age 10. Research results indicate the current vaccine is about 85% effective in preventing an outbreak. Comprehensive accounts of chickenpox^ref and chickenpox vaccination^ref are available at the CDC website. Varicella is the most common fatal

'childhood disease' in the USA^ref. Varicella ranks 4th among all vaccine-preventable deaths^ref
=> at 1^st infection (90% before age 9) from ...
• inhalatory or conjunctival route : primary viremia and secondary viremia in RES cells => after 10-23 days incubation =>
• varicella / chickenpox:maculopapular exanthema => vesicles (Sklowsky's symptom : when light pressure with the index finger is made upon the healthy skin near, and then over, a vesicle in varicella, the wall of the vesicle easily collapses and the contents are discharged) => pustules with "starry sky" look (contemporaneous presence of papulae, vesicles and scubs on whole body). + salicylates (+ Influenzavirus A H₃N₂ ?) => Reye's syndrome . Sequelae : vesicles, impetigo, neuraxitis, acute glomerulonephritis, acute hepatitis, keratitis, interstitial pneumonia (1%, expecially in immunocompromised adults => death due to respiratory failure), postvaricella purpura fulminans (due to autoimmune thrombocytopenia and DIC),  lupus anticoagulant (LAC), cerebellitis (=> ataxia), post-infective encephalitis (PIE : 1 case out of 4,000-10,000), overinfection by Streptococcus pyogenes (expecially necrotizing fasciitis and TSLS) => thrombosis. Lifelong presence of neutralizing antibodies prevents reinfection. Virus undergoes latency in satellite cells of a sensitive ganglion.
• modified varicella-like syndrome (MVLS) in vaccinated individuals : shorter and milder
• transplacental route :
• if mother becomes affected before pregnancy month 4 => eye, brain and limbs injuries in newborn
• if mother becomes affected just 5 days before the birth => 30% lethality in newborn
=> endogenous reactivation during cell mediated immunity depression => (herpes) zoster / zona / shingles on the unilateral dermatomere innerved by the sensitive nerve in whose dorsal ganglion VZV had undergone latency :
• thoracic zoster / Saint Antony fire (T3-T12 dermatomere) > lumbar zoster (L1-L2 dermatomere) > cervical zoster > herpes zoster ophthalmicus (HZO) (if reactivation occurs in ophthalmic or nasociliary branch of trigeminal nerve innervating V1 dermatomere : keratoconjunctivitis and iridocyclitis)
Ramsay-Hunt syndrome if reactivation occurs in geniculate ganglion of facial nerve
herpes zoster oticus if reactivation occurs in uditive nerve
visceral herpes zoster if reactivation occurs in a orthosympathetic or parasympathetic ganglion. Particularly in allogeneic HSCT recipients, visceral disease may precede or occur in the absence of the characteristic signs on the skin^{ref1, ref2, ref3, ref4}. In such cases, in which patients present with severe unexplained abdominal pain, diagnosis and treatment are usually delayed until signs of the infection appear on the skin or, in the absence of a rash, the diagnosis is made at necropsy. In allogeneic BMT recipients, the symptoms may be misdiagnosed as graft-versus-host disease, and immunosuppressive treatment instituted, with potentially grave consequences^ref. In view of the significant morbidity and mortality, early diagnosis of visceral involvement of herpes zoster is highly desirable. A case series of 4 patients with visceral herpes zoster was reported in whom large concentrations of DNA from VZV were detectable in blood by PCR^ref before signs of infection appeared on the skin, thus enabling early diagnosis and treatment^ref
encephalomyelitis
disseminated zoster occurs only in immunodepressions => herpes zoster duplex asymmetricus, interstitial pneumonia, encephalitis
=> post herpetic neuralgia (PHN) : pain that lasts for months to years. More common the older with increasing age and with zoster of the face
=> multiple sclerosis : VZV DNA was detected more frequently (P < 0.05) in the CSF of MS group (31.6%), particularly among the relapsing-remitting MS patients (43.5%), compared with patients with other neurological diseases (10.7%)^ref
An outbreak of cadaver-acquired chickenpox in a health care setting during necropsy^ref
Patients with disseminated, recurrent, or gangrenous zoster, with postherpetic neuralgia, and with ophthalmic zoster are not at elevated risk for subsequent cancer^ref
Laboratory examinations :
• scraping => Tzanck cells, Cowdry type A inclusion bodies, balloon-like CPE
• PCR
• serology :
• anti-VZV IgM at ELISA
• specific IgG avidity index (AI)^ref
Prophylaxis : attenuated vaccine protects from primary infection but not from reactivations; the only way to prevent shingles is eradication via massive antiviral drugs (vidarabine, acyclovir) while having chickenpox, before the virus shelters into ganglia (where drugs can't reach it).
Therapy :
• acyclovir (prodrug : valacyclovir) or famciclovir
• alcoholic^ref or aqueous^refpovidone-iodine
• homologous immune antiserum
• a single epidural injection of steroids and local anaesthetics can lessen pain associated with shingles for 1 month, but the treatment is not effective for the prevention of long-term pain^ref
pseudorabies virus (PrV) / Aujeszky's disease virus (ADV) / suid herpesvirus 1

Receptor : glycoprotein D (gD) binds to herpesvirus entry protein B (HveB) / poliovirus receptor-related 2 (PVRL2) / CD112 / CD155 and herpesvirus entry protein C (HveC) / poliovirus receptor-related 1 (PVRL1) / nectin-1 / herpesvirus Ig-like receptor (HIgR)
Transmission : pseudorabies is most often spread by direct contact between animals but may also be spread by aerosolization. People may carry the virus on their boots, clothing, on trucks or feed equipment between infected sites and non-infected sites ; the virus can remain hidden in nerves of Sus scrofa in a carrier state for long periods of time and then be reactivated. Once introduced into a herd the virus usually remains there and it can continually affect reproductive performance at varying levels. The virus can survive for up to 3 weeks outside the pig. The virus crosses the uterus and placenta and infects the foetuses.
=> Aujeszky's disease :
• pig is the main host :
• sows : cough, fever, nervous signs, reproductive failure, abortions, mummified piglets, stillbirths, birth weak litters. Swine generally appear asymptomatic, and the 1st noticed signs may be abortion, or a high mortality in piglets. Mortality in pigs under a month old may be close to 100%, but only about 10% in pigs as old as 6 months. Other clinical signs include fever, depression, coughing, sneezing, constipation, seizures, ataxia, and circling. Excess salivation may be noticed in both piglets and mature pigs.
• piglets : nervous signs, incoordination, sneezing, coughing, high mortality, low / poor viable piglets
The presence of other infections such as porcine reproductive and respiratory syndrome (PRRS) virus and Leptospira spp. may increase the severity of disease.
• Canis familiaris, Felis catus, ... : nervous signs, death. Infected cattle and sheep show signs of pseudorabies by scratching and biting themselves. Pseudorabies in dogs and cats may manifest itself as sudden death. In cattle, signs include intense itching followed by neurological signs and death. In dogs, signs are evidenced by intense itching,

paralysis of the jaw and pharynx, howling, and death. In cats sudden death without clinical signs often occurs.
• weaners & growers : fever, sneezing, coughing, interstitial pneumonia. Nervous signs including incoordination, fits, Aujeszky's itch / mad itch, and meningitis. Some strains of the virus can cause severe respiratory disease and others severe acute rhinitis. Usually low mortality. However, the pathogenicity to human is controversial : maybe it is dangerous only for immunocompromised hosts.
• Betaherpesvirinae
• Cytomegalovirus
• human herpesvirus 5 (HHV-5) / human cytomegalovirus (CMV) (HCMV) / cytomegalic inclusion disease virus / salivary gland virus
Proteomics : HCMV initially binds to cell-surface heparan sulphate proteoglycans (HSPGs)^ref
• envelope glycoprotein B (gB) / UL55 (4-5 genotypes) binds the receptors
• EGFR : B preferentially binds EGFR and EGFR-ErbB3 oligomeric molecules^ref. HCMV infection results in a rapid decrease in EGFR expression, which implies that the interaction between HCMV and EGFR occurs at an early stage of virus and host contact^ref
• CD209 / dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN) / CIRE on monocytes (and DCs) and neutrophils (leukotropism)
• annexin II^ref
=> endothelial cells (infected via apical membranes => disrupted cell junction proteins => altered paracellular permeability and cell polarity; if uterine microvascular endothelial cell (UtMVEC) are infected => endovascular cytotrophoblasts => retrograde placental infection), where then it undergoes latency. PMNLs contribute the greatest to the overall viral load in blood (median viral load: PMNLs, 10(5.37) genomes/mL of blood; monocytes, 10(4.40) genomes/mL; B cells, 10(3.70) genomes/mL; and T cells, 10(4.08) genomes/mL). However, monocytes have a viral burden of 0.65 genomes/monocyte which is greater than that within the other leukocyte populations.
• glycoprotein H (gH) binds the coreceptor integrins a₂b₁, a₆b₁, and a_vb₃, which then translocates to lipid rafts where it interacts with EGFR to induce coordinated signaling. The coordination between EGFR and a_vb₃ is essential for the early events of HCMV infection, including viral entry, RhoA downregulation, stress-fiber disassembly and viral nuclear trafficking^ref
• early antigen / pp65 matrix protein binds to NKp30 and inhibits NK cell cytotoxicity^ref
• IE-84 inhibits p53
• m04, m06 and m152 genes are important in evading the host immune system by interfering with the MHC class I pathway
• UL16 glycoprotein binds activating receptor NKG2D ligands UL16 binding proteins (ULBPs) and MICB, retaining them in the cell and effectively masking NK-cell recognition. gp40, the ortholog murine cytomegalovirus (MCMV) protein, disrupts the RAE-1-NKG2D interaction in mice by sequestering RAE-1 molecules, but not H60.
• UL18 is a putative NK lymphocyte decoy
• UL37 / viral mitochondrion-localized inhibitor of apoptosis (vMIA) is a Bcl-2 ortholog. that induces retention of MHC class II⁺ vesicles in an abnormal perinuclear distribution in DCs.
• UL21.5 protein is a small, secreted decoy for CCR whose mRNA is packaged into virions and functions as a high affinity decoy for CCL-5 / RANTES, modulating the host antiviral response even before the newly infecting viral genome becomes transcriptionally active^ref.
• UL144, an orphan TNFR, conserves the binding site on HVEM for BTLA : UL144 binds BTLA, but not LIGHT, and inhibits T cell proliferation, selectively mimicking the inhibitory cosignaling function of HVEM^ref
• US2 catalyse the dislocation of class I MHC products, resulting in the rapid degradation of HLA-DRa and HLA-DMa in DCs.
• US3 retains class I MHC complexes in the ER.
• US6 inhibits TAP
• US11 uses its transmembrane domain to recruit class I MHC products to Derlin-1, a human homologue of yeast Der1p, a protein essential for the degradation of a subset of misfolded ER proteins catalysed by US11, but not by US2^ref. Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER, as well as with VIMP, a novel membrane protein that recruits the cytosolic p97 ATPase and its cofactor^ref. US11 transports MHC class I H chains back into the cytosol, where they are deglycosylated by host N-glycanase and then degraded by the 26S proteasome
Epidemiology : seroprevalence :
age	heterosexuals	homosexuals	blood donors
18÷29	47.4 %	93.3 %	35.7 %
> 30	62.5 %	93.8 %	45.3 %
every age	54.3 %	93.5 %	42.7 %
Transmission => cytomegalic inclusion disease : any of a group of diseases caused by CMV infection, marked by characteristic inclusion bodies in enlarged infected cells.
• prenatal in utero infection by transplacental route => cytomegalic inclusions disease and IgA deficiency (?).
• post-natal or perinatal infectionin passage through the birth canal or from ingestion of virus in the mother's milk or transfusion : often asymptomatic, but in some there may be hepatosplenomegaly, jaundice, chorioretinitis, purpura, microcephaly, cerebral calcifications, and severe central nervous system sequelae with blindness, deafness, quadriplegia, and mental retardation. Viral excretion in the urine continues for years. The prevalence of maternal CMV infection is 1.2% and among these pregnant women, the incidence of primary and recurrent maternal CMV infection was 0.3% (3 women) and 0.8% (12 women), respectively. Congenital CMV infection was detected in one of the newborns born to mothers with primary infection while no infection was detected in any of the newborns of mothers with recurrent CMV infection, so the incidence of congenital CMV infection was found as 0.1% and the rate of intrauterine infection following the primary maternal infection was 33%^ref. Despite a very high CMV seropositivity rate in mothers of ELBW infants, and the previously reported high rate of CMV excretion into breast milk, the incidence of postnatal CMV transmission is about 2%^ref
• children and adults => acquired disease is transmitted via respiratory droplets, tissue or blood donation, or sexual transmission
• the majority of infections are asymptomatic
• Gianotti-Crosti syndrome (GCS) / papular acrodermatitis of childhood (PAC)
• cytomegalovirus mononucleosis with no pharyngotonsillitis and Downey type I atypical lymphocytes => immunodeficiency, cold agglutinin disease. Samples for direct diagnosis vary with time : oropharyngeal swab => blood => urine. Virus undergoes latency in PBMCs.
• autoimmune diseases :
• type IA diabetes mellitus
• rheumatoid arthritis
• systemic progressive sclerosis
• cardiovascular diseases (24% higher likelihood than unaffected ones)
• reactivation and reinfection in immunocompromised hosts are detected with pp65 antigenemia =>
• postperfusion or post-transfusion mononucleosis or syndrome : cytomegalovirus mononucleosis occurring about 3 to 6 weeks after extracorporeal circulation or multiple blood transfusions in open heart or other surgical procedures
• cytomegalovirus interstitial pneumonia
• myelopathies
• cytomegalovirus meningoencephalitis (Guillain-Barré syndrome)
• glandular involvement, gastro-intestinal ulceration with acute hepatitis
• endocrinopathies
• iridocyclitis and cytomegalovirus chorioretinitis ("pizza pie" look) fist monolateral, then bilateral
• decreased MHC class I expression may enhance NK cell-mediated solid organ allograft rejection :
• kidney transplantation
• acute tubulointerstitial rejection : CMV seromismatched patients (donor⁺/recipient^- or D⁺/R^-) have a 60-80% probability of primary CMV disease and a significantly higher rate of acute rejection than non-seromismatched patients (72% vs. 54.2%, P=0.005). Using multiple logistic regression, CMV seromismatch, delayed graft function, and biological induction were identified as independent predictors of acute rejection. The adjusted odds ratios for these are 2.28, 1.65, and 0.52, respectively. In such cases chemoprophylaxis is justified, at least in those patients who are are found to have 1 or more pp65⁺ cells per 150,000 peripheral WBCs examined (preemptive therapy)
• chronic allograft nephropathy (CAN) : the greater the viral load, the higher the risk of vascular lesion
Long-lasting expansion of Vd2^- gd T cells is a hallmark of HCMV infection in kidney transplant recipients. The ligands of these cells and their role remain elusive. To better understand their immune function, gd T cell clones were generated from several transplanted patients. Numerous patient Vd1⁺, Vd3⁺, and Vd5⁺ gd T cell clones expressing diverse V chains, but not control Vg9Vd2⁺ T clones, displayed strong reactivity against CMV-infected cells, as shown by their production of TNF-a. Vd2^- gd T lymphocytes could also kill CMV-infected targets and limit CMV propagation in vitro. Their anti-CMV reactivity was specific for this virus among herpesviridae and required TcR engagement, but did not involve MHC class I molecules or NKG2D. Vd2^- gd T lymphocytes expressed receptors essential for intestinal homing and were strongly activated by intestinal tumor, but not normal, epithelial cell lines. High frequencies of CMV- and tumor-specific Vd2^- gd T lymphocytes were found among patients' T cells. In conclusion, Vd2^- gd T cells may play a role in protecting against CMV and tumors, probably through mucosal surveillance of cellular stress, and represent a population that is largely functionally distinct from Vg9Vd2⁺ T cells^ref
• vasculopathy leading to cardiac allograft rejection
• lung transplantation chronic rejection
• liver transplantation chronic rejection
• triggers autoantibody formation against CD13 in transplanted patients which, in turn, has been shown to be associated with the development of chronic GvHD
See also the impact of CMV serostatus in allogeneic HSCT
Laboratory examinations :
• IgM (< 0.4 UA/mL => negative; 0.901-0.5 UA/mL => repeat after 10 days; > 0.5 UA/mL => positive)
• IgG (< 15 UA/mL => negative; > 15 UA/mL => positive)
• specific IgG avidity index (AI)^ref
• pp64 antigenemia
• balloon-like CPE, Cowdry type A inclusion bodies, owl-eye inclusions
• ELISA
• DNA fingerprinting
• rapid-flow cytometry T-cell-based approach may represent a reliable alternative for defining CMV status in any clinical situation where serologic testing is limited by borderline titers or by the presence of passively administered antibodies^ref.
• the diagnostic value of the detection of CMV in BAL, which is high in allogeneic BMT recipients with pneumonia and low in patients with acquired immunodeficiency syndrome, has not been determined in autologous BMT recipients^{ref1, ref2}
Therapy :
• antivirals :
• acyclovir is not effective due to lack of tk
• effectiveness of ganciclovir oral chemotherapy (5 mg / kg IV or 1000 mg q8h PO) has been shown in SYNTEX 1654 trial (patients affected by both HIV-1 and CMV). Alternatively 5 mg/kg i.v. twice daily with adjustment for renal function : if resistance occurs (demonstrated by plaque reduction assay or quantitative CMV-DNA hybrid capture assay showing deletions in the UL97 codon range 591-607) =>
• foscarnet (resistance conferred by mutation in the DNA polymerase gene at codon 756 (E-D substitution). However, foscarnet resistance mutations that have been confirmed by marker transfer do not confer crossresistance to cidofovir^{ref1, ref2}.3, 18 )
• cidofovir
• leflunomide alone (induction dose 200 mg/day for 7 days, followed by a maintenance dose of 50 mg/day, targeting a serum level of 60-80 mg/ml of the active metabolite A77 1726)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8} or in addition to foscarnet^{ref1, ref2} or ganciclovir^ref. Leflunomide is a new disease-modifying antirheumatic drug approved in 1998 in the United States for the treatment of rheumatoid arthritis^ref. Among its proposed mechanisms of action are inhibition of T- and B-cell proliferation by interference with the de novo pathway of pyrimidine synthesis via inhibition of the enzyme dihydroorotate dehydrogenase and inhibition of phosphorylation of specific tyrosine kinases involved in T- and B-cell activity^ref. Leflunomide is increasingly recognized as a potent immunosuppressive agent for the prevention and treatment of rejection in solid organ transplant recipients^ref. It has also been reported to have novel anti-CMV activity in vitro, utilizing a mechanism different from that of other antiviral agents^{ref1, ref2}. The mechanism of leflunomide antiviral activity is a topic of active research, but it does not appear to affect transcription of immediate-early or late viral genes or to inhibit viral DNA polymerase activity. It appears to inhibit virion assembly at a late stage by preventing viral nucleocapsids from acquiring their tegument^ref. As leflunomide does not affect DNA polymerase or other aspects of DNA replication of CMV, it would be expected not to show crossresistance with other agents. One previous anecdotal report suggested a response to leflunomide and cidofovir in a transplant patient with CMV resistant to ganciclovir and foscarnet. Leflunomide also appears to have antiviral activity against HSV as well^ref. Renal compromise may alter the efficacious blood level target^ref and patients with elevated serum creatinine may have substantially reduced protein binding; thus the effective (and toxic) level might be reduced. This has been cited as an explanation for significant variation in active metabolite pharmacokinetic features in a series of patients with chronic renal allograft dysfunction treated with leflunomide^ref
Although ganciclovir has been the mainstay of CMV treatment in the past, ganciclovir-resistant CMV in solid organ and bone marrow transplant recipients has been reported with increasing frequency over the past several years^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8,ref9}. Ganciclovir-resistant CMV has been seen frequently in AIDS patients with CMV retinitis, particularly those receiving lengthy courses of ganciclovir therapy^ref. It is thought that prolonged exposure to ganciclovir, particularly at concentrations that do not fully suppress viral replication, may lead to resistance^{ref1, ref2, ref3, ref4}. Ganciclovir resistance may be assessed by phenotypic analysis by plaque reduction assay^{ref1, ref2} and by genotypic analysis, which demonstrates characteristic mutations in the UL97 region or the DNA polymerase gene^{ref1, ref2, ref3, ref4}. In the past, foscarnet has been the main agent utilized for therapy for ganciclovir-resistant CMV in transplant recipients^ref, but its usefulness in transplant recipients is often limited by nephrotoxicity and electrolyte disturbances. Combination ganciclovir and foscarnet therapy has been utilized in AIDS patients with retinitis (Combination foscarnet and ganciclovir therapy vs monotherapy for the treatment of relapsed cytomegalovirus retinitis in patients with AIDS. The Cytomegalovirus Retreatment Trial. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Arch Ophthalmol 1996; 114: 23-33) and in allogeneic stem cell recipients^ref. Recent work suggests that a combination of reduced-dose ganciclovir and foscarnet may be effective and less toxic for ganciclovir-resistant CMV in solid organ transplant recipients^ref. Cidofovir, the third FDA-approved drug for the treatment of CMV^ref, has been used primarily for retinitis in AIDS patients and for CMV in allogeneic stem cell recipients^ref. However, cidofovir is also potentially highly nephrotoxic, and crossresistance between ganciclovir and cidofovir has been described^{ref1, ref2} when mutations occur in the UL54 region^ref. Resistance to foscarnet, to cidofovir, and multiple resistance have been described^{ref1, ref2, ref3, ref4}. A reports described systemic therapy for CMV refractory to all 3 standard drugs^ref
• homologous immune antiserum. Treatment of pregnant women with primary CMV infection with CMV-specific monthly hyperimmune globulin (100 U/kg i.v.). is safe, and the findings of this nonrandomized study suggest that it may be effective in the treatment and prevention of congenital CMV infection. A controlled trial of this agent may now be appropriate^{ref1, ref2}
Web resources : The World of Human Cytomegalovirus
• Simian cytomegalovirus (SCMV)
=> chronic fatigue syndrome (CFS)
=> encephalopathy (psychoses, ...)
• Roseolovirus
• Human herpesvirus 6A (HHV-6A) / human B-lymphotropic virus (HBLV)

Epidemiology : discovered in 1986^ref; the peak age of acquisition is between 9 and 21 months^ref. In common with other herpes viruses, HHV6 also tends to show persistence and intermittent or chronic shedding in the normal population, making the unusually early infection of children understandable (seroconversion in the first year of life in up to 80% of all children, 90% of children by 2 years of age). This means that HHV6 infections manifesting in close temporal association with recommended vaccinations may be misinterpreted as complications of the vaccination. Today, the situation can be clarified by employing special virological-serological laboratory tests, which are available throughout the country. HHV-6 genome is found in 11% of peripheral blood samples and in 28% of the bone marrow samples from healthy volunteers^ref
Proteomics : glycoprotein H-glycoprotein L-glycoprotein Q complex  binds to CD46 / MCP (expressed ubiquitously in human tissues); it induces syncytium formation of diverse human cells 2 h after infection by fusion from without (FFWO)
=> in immunocompromised individuals :
• fulminant hepatitis
• interstitial pneumonia
• Gianotti-Crosti syndrome (GCS) / papular acrodermatitis of childhood (PAC)
• pityriasis rosea^ref (at a lesser extent than HHV-7^ref), but so far there is not enough evidence for a pathogenetic association of HHV-7 with this exanthematic skin disease^ref. Pityriasis rosea in pregnancy--specific diagnostic implications and management considerations^ref
• lymphoproliferative disorders : HHV-6 activation was documented in 34% of cases of non-Hodgkin's lymphoma (NHL) and 39% of those of Hodgkin's lymphoma; however, no correlation of activation status with pathological types of Hodgkin's disease and between copy numbers in peripheral blood mononuclear cell DNA and the corresponding plasma DNA was noticeable^ref.
• Hodgkin's lymphoma (?)
• Burkitt's lymphoma^ref
• angioimmunoblastic lymphoma
• chronic fatigue syndrome (CFS)
• Langerhans cell histiocytosis (LCH) (?)
• HHV-6 DNA was detected in PBL in 74% of autologous recipients and 76% of allogeneic recipients, and in biopsy tissue in 48% of autos and 71% of allos. However, HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting an association (P = 0.004) between HHV-6 DNA in biopsy tissue and GVHD severity. A significant linear trend (P = 0.03) was identified between detection of HHV-6 DNA in biopsy tissue obtained prior to or concomitant with the onset of GVHD and increased GVHD severity, suggesting that HHV-6 was causally linked to GVHD rather than reactivated as a consequence of GVHD therapy^ref
It worsens HIV-1 mediated CPE in super-infections of CD4⁺ T-lymphocytes : a 3.9-kbp SalI-L DNA fragment spanning the junction of the direct repeat left (DRL) and unique long segment (UL) regions of HHV-6 up-regulates HIV-1 LTR CAT 10-15 fold in both monkey CV-1 and human T Jurkat cells^ref.
• Human herpesvirus 6B (HHV-6B) / human B-lymphotropic virus (HBLV)

Proteomics : glycoprotein H-glycoprotein L-glycoprotein Q complex  binds to CD46 / MCP (expressed ubiquitously in human tissues); it induces syncytium formation of diverse human cells 2 h after infection by fusion from without (FFWO)
Transmission : older siblings appear to serve as a source of HHV-6 transmission.
=> roseola (infantum) / exanthem or exanthema subitum / rose rash of infants / "sixth" disease (to differentiate it from other exanthems) : an acute, short-lived mononucleosis-like syndrome of infants and young children (expecially between month 6 and age 2) after 5-15 days incubation; after a high fever of 3 to 4 days' duration, occipital lymphadenitis, laterocervical lymphadenitis and retroauricular lymphadenitis the temperature suddenly drops to normal; either shortly before, simultaneously with, or shortly after this happens, a macular or maculopapular rash appears on the trunk and spreads to other areas for 1-2 days.  Downey type III atypical lymphocytes. Complications :
• meningoencephalitis (=> febrile convulsions (with and without exanthem)); usually fatal when it is resistant to antiviral drugs unless treated with donor lymphocyte infusions (DLIs)^ref
• fulminant hepatitis
• lethal disseminated infections
• untypical exanthem or uncharacteristic rash (with and without fever)
• acute respiratory disease (ARD)
• acute gastroenteritis
• complications of ARD (sinusitis, otitis media, bronchial pneumonia)
• Pfeiffer's disease (mononucleosis-like syndrome)
• drug rash with eosinophilia and systemic symptoms (DRESS)
• in individuals with a relevant disposition (genetic HLA/DR type) initiation or (re-)activation of juvenile chronic arthritis (JCA) or chronic iridocyclitis may occur
• HHV-6 promotes the expression of HHV-4 / EBV antigen (may contribute to the pathogenesis of nasopharyngeal carcinoma in cooperation with EBV^ref) and activates lytic cycle replication of HHV-8 / KSHV^ref
Virus undergoes latency => reactivation during immunodepressions => interstitial pneumonia
Roseola occurs in a minority of patients, and febrile seizures are infrequently associated with primary HHV-6 infection
=> Alzheimer's disease (?)
• unclassified Betaherpesvirinae
• Human herpesvirus 7 (HHV-7)
Epidemiology : discovered in 1989^ref. Primary infection occurs early in life. HHV-7 genome is found in 67% of peripheral blood samples and in 50% of the bone marrow samples from healthy volunteers^ref
=> macular-papular rashes in children (exanthema subitum, or other febrile illnesses mimicking measles and rubella.
=> other inflammatory skin disorders, such as psoriasis and papular-purpuric gloves-and-socks syndrome, but has also been found to occur in normal dermal tissues. There are controversial data on the detection of HHV-7 (at a greater extent than HHV-6^ref) in pityriasis rosea^ref (primary infection > reactivation^ref), but so far there is not enough evidence^{ref1, ref2, ref3, ref4}
=> although HHV-7 can be found in some cases of Hodgkin's lymphoma, there are no data supporting a direct causative role in this lymphoma type nor in other nodal or primary cutaneous lymphomas
=> reactivation of HHV-6.
=> in various epidemiologic forms of Kaposi's sarcoma, infection of monocytic cells with HHV-7 was demonstrated, which may indirectly influence tumor biology
=> in the context of immunosuppression, HHV-7 has recently been identified as an emerging pathogen in transplant recipients and may exacerbate graft rejection in renal transplant recipients.
The ability of HHV-7 to induce cytokine production in infected cells could make HHV-7 an important pathogenetic co-factor in inflammatory and neoplastic disorders. Moreover, the restricted cellular tropism of HHV-7 may render this virus an interesting vector for gene therapy^ref
• Gammaherpesvirinae / lymphocyte-associated virus (lymphoproliferative virus group)
• Lymphocryptovirus / gamma-1 herpesviruses
• Human herpesvirus 4 (HHV-4) /  Epstein-Barr virus (EBV) / EB virus
• Rhadinovirus / gamma-2 herpesviruses
• Human herpesvirus 8 (HHV-8) / Kaposi's sarcoma-associated herpesvirus (KSV / KSHV)
• subacute myelo-optic neuropathy (SMON) virus / Inoue-Melnick virus (IMV)
• type I
• type II
Epidemiology : epidemics in Japan (1960's), Cuba (1991-1993) and Tanzania (1988-2003). A possible connection between Tanzania & Cuba may is that the Cuban military were in Tanzania before 1976, not as combatants but as coordinators of Cuban forces fighting in other African countries
=> subacute myelo-optic neuropathy (SMON) : a clinical syndrome affecting the spinal cord, optic nerve, and peripheral nerves, preceded by diarrhea. Symptoms include paresthesia in both lower limbs, gait disturbances, visual disturbances, abnormalities of deep tendon reflexes, and psychic disorders. The hydroxyquinolones (especially clioquinol), taken for gastrointestinal disorders, have been implicated as an etiologic factor
• Papillomaviridae


(reproduced with permission from Nature Reviews Immunology (Vol 4, No. 1, pp 46-55 (2004)) copyright Macmillan Magazines Ltd)
• Papillomavirus : papillomaviruses; a genus of viruses family Papovaviridae that induce papillomas in humans and in many animal species. Papillomaviruses are highly species-specific and have a tropism for squamous epithelium; some have been associated with malignancy
• Human papillomavirus (HPV)
• Human papillomavirus type 1a
=> slaughterers' wart
=> verruca plana / plane wart
=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
=> verruca vulgaris / common wart
• Human papillomavirus type 2
=> epidermodysplasia verruciformis with macules
=> verruca vulgaris / common wart
=> lip lesions
=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
=> slaughterers' wart
=> flat condyloma of cervix
• Human papillomavirus type 2a
• Human papillomavirus type 2c
• Human papillomavirus type 3
=> flat condyloma of cervix
=> slaughterers' wart
=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 4
=> verruca vulgaris / common wart
=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
=> slaughterers' wart
=> flat condyloma of cervix
• Human papillomavirus type 5

=> epidermodysplasia verruciformis
• Human papillomavirus type 5b
• Human papillomavirus type 6
=> anogenital wart / exophytic condyloma / condyloma acuminatum
=> flat condyloma of cervix
=> weak association with cervical carcinoma
=> conjunctival papilloma
=> laryngeal papilloma
=> Heck focal epithelial hyperplasia (?)
• Human papillomavirus type 6a
• Human papillomavirus type 6b
• Human papillomavirus type 6c
• Human papillomavirus type 6e
• Human papillomavirus type 6vc
• Human papillomavirus type 7
=> slaughterers' wart
• Human papillomavirus type 8

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 9

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 10
=> epidermodysplasia verruciformis with macules
=> verruca plana / plane wart
=> slaughterers' wart
=> weak association with cervical carcinoma
• Human papillomavirus type 11
=> laryngeal papilloma
=> conjunctival papilloma
=> Heck focal epithelial hyperplasia (?)
=> epidermodysplasia verruciformis
=> anogenital wart / exophytic condyloma / condyloma acuminatum
=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 12

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 13
=> Heck focal epithelial hyperplasia
• Human papillomavirus type 14
• Human papillomavirus type 14D
=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 15

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 16
Proteomics : E7 gene encodes a multifunctional oncoprotein that can subvert multiple cellular regulatory pathways :
• retinoblastoma tumor suppressor protein pRB
• the related pocket proteins p107 and p130
• 600-kDa retinoblastoma protein associated factor, p600 (independent of the pocket proteins and is mediated through the N terminal E7 domain, which is related to conserved region 1 of the adenovirus E1A protein and importantly contributes to cellular transformation independent of pRB binding)^ref
=> laryngeal papilloma
=> Heck focal epithelial hyperplasia (?)
=> flat condyloma of cervix
=> strong association with cervical carcinoma (cervical intraepithelial neoplasia (CIN)). Higher crude viral load, as determined by RT-PCR targeting the E7 gene, was observed for SCC but became insignificant after normalization for cell content. Integration was located and quantified by real-time PCRs targeting, respectively, the carboxyl, amino, and hinge domains of the E2 gene. Pure episomal, integrated, and mixed forms were observed in all disease groups. Most E2 gene disruptions involved the amino-terminal, but sparing the hinge region that has been frequently used as a surrogate marker of integration. Large-fragment disruption involving all 3 E2 regions was observed only in the CIN 3 and SCC groups. Altogether, 33.3% of the CIN 3 group and 28.0% of the SCC group harbored pure episomal genomes. The Asian lineage was associated with a higher risk for CIN 3/SCC than the European lineage, and 6 of the 7 large-fragment E2 disruptions were from Asian lineage. The link between viral lineage, integration pattern, and oncogenesis deserves further study^ref.
=> vulvar carcinoma
=> penile intraepithelial neoplasia (PIN)
=> bowenoid papulosis
=> in 29% of breast carcinoma and metastatic lymph nodes using PCR^ref; in both breast and cervical cancer tissues in Norwegian women with concurrent breast carcinoma and cervical carcinoma^ref
• Human papillomavirus type 17

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 18

=> flat condyloma of cervix
=> strong association with cervical carcinoma (cervical intraepithelial neoplasia (CIN)). In most cases the immune system knocks the virus out before it can do any damage. In some cases, however, the infection becomes chronic, with measurable levels of the virus remaining in the system. Perhaps 5% of these women will eventually develop precancerous lesions that could lead to cervical cancer. Or at least that's what would happen if they did not undergo routine Pap smears, which can detect abnormal cervical tissue before it turns malignant.
• Human papillomavirus type 19

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 20

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 21

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 22

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 23

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 24

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 25

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 26

=> verruca vulgaris / common wart
=> weak association with cervical carcinoma
• Human papillomavirus type 27

=> verruca plana / plane wart
=> verruca vulgaris / common wart
• Human papillomavirus type 28
=> verruca vulgaris / common wart
=> slaughterers' wart
• Human papillomavirus type 29

=> verruca vulgaris / common wart
• Human papillomavirus type 30
=> laryngeal papilloma
• Human papillomavirus type 31

=> flat condyloma of cervix
=> strong association with cervical carcinoma
• Human papillomavirus type 32
=> Heck focal epithelial hyperplasia
• Human papillomavirus type 33

=> moderate association with cervical carcinoma
=> breast carcinoma of 41% of Chinese and 11% of Japanese women^ref
• Human papillomavirus type 34
• Human papillomavirus type 35
• Human papillomavirus type 35H
=> moderate association with cervical carcinoma
• Human papillomavirus type 36

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 37

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 38

=> epidermodysplasia verruciformis with macules
=> verruca plana / plane wart
• Human papillomavirus type 39

=> penile intraepithelial neoplasia (PIN)
=> moderate association with cervical carcinoma
• Human papillomavirus type 40

=> penile intraepithelial neoplasia (PIN)
=> weak association with cervical carcinoma
• Human papillomavirus type 41

=> verruca vulgaris / common wart
• Human papillomavirus type 42

=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 43

=> weak association with cervical carcinoma
• Human papillomavirus type 44

=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 45

=> strong association with cervical carcinoma
• Human papillomavirus type 47

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 48
• Human papillomavirus type 49

=> wart in transplanted individuals
=> verruca plana / plane wart
• Human papillomavirus type 50

=> epidermodysplasia verruciformis with macules
• Human papillomavirus type 51

=> moderate association with cervical carcinoma
• Human papillomavirus type 52

=> moderate association with cervical carcinoma
• Human papillomavirus type 53

=> weak association with cervical carcinoma
• Human papillomavirus type 54

=> flat condyloma of cervix
=> weak association with cervical carcinoma
• Human papillomavirus type 55

=> bowenoid papulosis
• Human papillomavirus type 56

=> moderate association with cervical carcinoma
• Human papillomavirus type 57
• Human papillomavirus type 57b
=> verruca vulgaris / common wart
• Human papillomavirus type 58
=> moderate association with cervical carcinoma
• Human papillomavirus type 59
=> moderate association with cervical carcinoma
• Human papillomavirus type 60
• Human papillomavirus type 61
=> weak association with cervical carcinoma
• Human papillomavirus type 62

=> weak association with cervical carcinoma
• Human papillomavirus type 63

=> verruca palmaris or verruca plantaris (myrmecia or palmoplantar wart)
• Human papillomavirus type 64
• Human papillomavirus type 65

=> verruca vulgaris / common wart
• Human papillomavirus type 66
• Human papillomavirus type 67
• Human papillomavirus type 68
=> moderate association with cervical carcinoma
• Human papillomavirus type 69
• Human papillomavirus type 70
• Human papillomavirus type 71
• Human papillomavirus type 72
• Human papillomavirus type 73
• Human papillomavirus type 74
• Human papillomavirus type 75

=> verruca plana / plane wart
• Human papillomavirus type 76

=> verruca plana / plane wart
• Human papillomavirus type 77

=> verruca vulgaris / common wart
• Human papillomavirus type 80
• Human papillomavirus type 82
• Human papillomavirus type 83
• Human papillomavirus type 84
• Human papillomavirus type 86
• Human papillomavirus type 87
• Human papillomavirus type JC9710
• human papillomavirus type JC9813
• Human papillomavirus type me180
• Human papillomavirus type RTRX7
• human papillomavirus type Xc
• human papillomavirus type Xd
• human papillomavirus type Xf
• human papillomavirus type Xg
• human papillomavirus type Xh
Epidemiology : HPV is a common infection in the general population (about 630 million women worldwide are infected with sexually transmitted HPVs). HPV association with genital warts was discovered in 1907 by the Italian scientist, Ciuffo.
=> 1% of sexually active adults (aged 15-49 years) either have or have had genital warts. In the remaining sexually active population without warts HPV is pervasive with > 50% having subclinical or latent infection. The peak prevalence occurs in men and women aged 17 to 33 years and the peak incidence in those aged 20 to 24 years. HPV is highly infective and a transmission rate after a single encounter has been reported to be as high as 26%. In 10-20% of patients spontaneous resolution of their disease will occur within 3-4 months. Current therapies may have little effect on eradication of HPV or transmission of infection and have recurrence rates of 30-70% within 6 months of end of treatment.
=> all types can also cause subclinical infections and the immune response to the virus protects against chronic infection that can lead to cancer. In a minority of individuals the immune response seems not to be strong enough or of the right type, allowing the establishment of chronic infection.
Genomics :
• human loci
• human papillomavirus (type 18) integration site 2 (HPV18I2) (a heritable fragile site)
• human papillomavirus (type 6a) integration site 1 (HPV6AI2) (contains the site of breakpoints affecting protooncogenes Hox11 and Lyt10)
• human papillomavirus (type 18) E5 central sequence-like 1 (HPVC1)
• papillomavirus regulatory factor (PRF)-1 /papillomavirus binding factor (PBF)  recognizes the sequence CCGG, which represents the 3' half of the E2 binding sites of papillomaviruses which mediate transcriptional repression by E2
• RUNX1 / CBF binds to the repression-mediating E2 binding site P2 of HPV8
• papillomavirus L2 interacting nuclear protein 1 (PLINP-1)
Proteomics : gene expression and vegetative replication occur exclusively in epithelial cells, confined to cells in the upper spinous or granular layers of squamous epithelia. Production of sufficient amounts of viral proteins and virion-assembly takes place only in cells destined eventually for desquamation and death.
• early genes :
• E1 is a DNA helicase that assists episomal replication; it is produced in + amount and has nuclear localization. It interacts with thyroid hormone receptor interactor 13. No natural immune response
• E2 is a transcription factor (nuclear localization) produced in + amounts that regulates HPV gene expression by sequence-specific DNA binding to E2 binding sites or Sp1 binding sites (p21(WAF1/CIP1)). It binds to C/EBP factors and may contribute to enhancing keratinocyte differentiation, which is suppressed by the viral oncoproteins E6 and E7 in HPV-induced lesions. It interacts with topoisomerase (DNA) II binding protein (TOPBP1) and G protein pathway suppressor 2 (GPS2) activating transcription of HPV genes. It targets ADA3 protein for degradation. Cellular responses are associated with regressing lesions in infected animals
• E3
• E5 is produced in + amounts and has cytoplasmic localization. It prevents cell differentiation (more important for BPV than HPV). It impairs TRAIL-mediated apoptosis by impairing DISC formation, and FasL-mediated apoptosis by downregulating Fas expression. No natural immune response
• intermediate genes
• E6 is produced in + amount and has nuclear localization. It prevents cell differentiation and interacts with ubiquitin protein ligase E3A (UBE3A) resulting in ubiquitination and proteolysis of tumor protein p53. It represses IL-8 transcription through effects on CREB binding protein/p300 and P/CAF. It interacts with karyopherin (Kap) a₂ and via its basic nuclear localization signal (NLS) located at the C terminus, with both Kap b₁ and Kap b₂ import receptors. It  targets the MAGI-2 and MAGI-3 proteins for degradation. It binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis.
• E7 is produced in ++ amount and has nuclear localization. It prevents cell-growth arrest/differentiation by inhibiting inhibitors of E2F transcription factor. Eg LXCXE peptide motif inactivates pRbby binding 3 regions of the pocket domain and inhibits the DNA interaction of the TATA binding protein. DTH is associated with regressing CIN lesions in humans. Antibody associated with invasive cervical cancers in humans
• E8 represses IL-8 transcription through effects on CREB binding protein/p300 and P/CAF
• late genes
• L1 major capsid protein (structural) is produced in ++++ amount and has nuclear localization; antibody in 50-100% of infected humans, occurring weeks to years after infection; HPV11 L1 interacts with Kap b₂ and Kap b₃ nuclear import receptors
• L2 minor capsid protein is produced in ++ amounts and has nuclear localization assisting packaging of DNA; mRNA translation is controlled by poly(rC) binding protein 1 (PCBP1) and and PCBP-2; no natural immune response
• E4 is produced in +++ amount and has cytoplasmic localization, assisting packaging of virus (?). No natural immune response
Why human papillomavirus is a poor natural immunogen :
• HPV is a dsDNA virus with no dsRNA intermediate to einvoke innate immune responses
• HPV mainly encodes non-secreted nucleoproteins, which are not effectively cross-presentede by infected cells
• most viral non-structural proteins are expressed at low levels compared with more immunogenic proteins from other viruses
• the virus only infects epithelial cells - an anti-inflammtory environment (IL-10 and TGF-b predominate)
• infection induces cell proliferation rather than cytolysis, without danger signals or antigen release to invoke innate immunity
• infection has no viraemic phase, as infected cells do not undergo lysis as a result of infection, and therefore less systemic antigen presentation occurs.
Laboratory examinations :
• electron microscopy. Only applicable in benign lesions as in malignant lesions the viral DNA is integrated and viral particles are not produced.
• IHC can detect major capsid protein but are generally group specific not type specific
• PCR : at present the only commercial test available is the Hybrid Capture^TM test which will differentiate between oncogenic and non-oncogenic HPV infections.
Prevention :
• subunit vaccines
• topical microbicides : carrageenan, an inexpensive, widely available compound extracted from red algae and used as a thickening agent in everyday products such as toothpaste and yoghurt, is highly effective at preventing the spread of the sexually transmitted HPV. The cheap ingredient was found to be effective at a concentration 100 times lower than the best HPV inhibitor currently on the market. Carrageenan was already known to be an inhibitor against the AIDS-causing virus HIV, and is currently undergoing clinical trials for that. The compound is also already used in a variety of sexual lubricants because of its gelling properties. Some of these over-the-counter products are decidedly effective against HPV transmission in the test-tube. The exciting thing is it is already available in various lubricants. The compound is easy to come by, and is classed as "generally regarded as safe" by the US Food and Drug Administration. Carrageenan, Irish for 'moss of the rock', is produced by boiling red seaweeds found in abundance along the rocky coasts of North America and Europe. Carrageenan acts like a border control, sticking to proteins on the HPV and preventing the virus from interacting with, or entering, the cells of the cervix. It seems to have a protective effect with some other viruses too, including the cold-sore-causing HSV. But HSV has an extra protective membrane that makes it less susceptible to carrageenan; a dose a thousand times greater was needed to achieve equivalent protection against HSV as was achieved against HPV. If carrageenan were added to an HIV microbicide, it could form one of the best preventatives against sexually transmitted diseases available. > 5,000 women in South Africa are currently taking part in phase 3 clinical trials of Carraguard, a vaginal gel containing carrageenan that has been designed to protect against HIV. These trials are due to end in 2007. Further trials will be designed to explicitly test the compound's effectiveness against HPV transmission. They are also working on developing a mouse model of HPV so that they can study it more closely in the lab^ref.
Therapy : for cutaneous warts, for genital warts
• [Papovaviridae : the papovaviruses: a family of DNA viruses having a nonenveloped icosahedral virion 40 nm (polyomaviruses) or 55 nm (papillomaviruses) in diameter with 72 capsomers in skew arrangement. The genome consists of a single circular molecule of double-stranded DNA (MW 3–5 ´ 106, size 5 kbp for polyomaviruses and 8 kbp for papillomaviruses). Viruses contain five to seven structural proteins and are resistant to ether, acids, and heat. Replication and assembly occur in the nucleus; virions are released by cell destruction. Host range is generally narrow; transmission is by contact or by airborne particles, and many species are oncogenic. There are 2 genera, Papovavirus and Polyomavirus]
• Polyomaviridae
• Polyomavirus: polyomaviruses; a genus of viruses of the Papovaviridae that induce tumors in experimental animals
Epidemiology : the polyomaviruses tend to have restricted host ranges, although cells which fail to support virus replication may become genetically transformed via the action of early gene products. In general, the polyomaviruses spread by reactivation of persistent infections in the mother during pregnancy, with low level shedding of virus in urine. The polyomaviruses often exhibit highly specific tissue-specific expression with frequent involvement of the kidney. human polyomaviruses are ubiquitous and exhibit a sero-prevalence of 60 to 80% in adults, but clinically relevant infections due to CPE on urothelium and epithelium are usually limited to individuals who are immunosuppressed
Pathogenesis : following a primary infection via the respiratory tract in childhood, these viruses are diffused in the blood using the B-lymphocytes during their latent stage in the urogenital tract. The reactivation that occurs after several years is asymptomatic and urinary excretion of BKV is observed in 4 to 6% of immunocompetent patients. They are mutagenic^ref. Sialic acid plays in determining viral tropism^ref.
• BK polyomavirus (BKV)
• BK virus strain AS
• BK virus strain GS
Epidemiology : seroprevalence rises significantly from 64% in 1-4-year-old children to 91% in 5-9-year-olds; titres decreasing linearly at a rate of 8.7% per 10 years^ref
Proteomics :
• receptor : BKV uses the terminal a2-8-linked disialic acid motif of gangliosides GT1b and GD1b as receptors and passes through the ER on the way to the nucleus^ref
Transmission : polyomaviruses are frequently present in stool samples from hospitalized children, suggesting that fecal-oral transmission of BKV may play a role in the ubiquity of infection^ref
=> tubulointerstitial nephritis (polyomavirus-associated neprhopathy (PVAN)) and ureteral stenosis in renal transplant recipients
=> hemorrhagic cystitis (HC) in bone marrow transplantation recipients. Architectural rearrangements in the non-coding control region (NCCR) of BKV did not appear to be a prerequisite for development of hemorrhagic cystitis in HSCT recipients^ref. C to G point mutations, within the BKV NCCR Sp1 binding site, were significantly more common in patients with HC, suggesting that these mutations may be indicative for the clinical diagnosis of HC and could influence the virulence of the virus^ref.
=> in episomal state, generally in a low copy number (0.2 to 2 genome equivalents per cell). :
• 44% of islet cell cancers^ref (including insulinoma^ref)
• 25.6% human brain tumors^ref
• 11 of 24 brain tumors of 11 different types^ref
There are increasing reports of BKV causing PVAN and HC in non-renal SOT recipients and other immunodeficiency diseases. This might be related to the use of more potent immunosuppressive regimens or increasing awareness of BKV as an important pathogen
Laboratory examinations : PCR in blood or biopsy, BKV nuclear inclusions can be seen
Therapy : reduction of immunosuppression, cidofovir
• JC virus (JCV)
• simian virus 40 (SV40)
• unclassified Polyomavirus
• JC virus x BK virus
• K virus : a nononcogenic virus of the genus Polyomavirus that produces fatal interstitial pneumonia on inoculation into newborn mice
• KI polyomavirus is phylogenetically related to other primate polyomaviruses in the early region of the genome but has very little homology (<30% amino acid identity) to known polyomaviruses in the late region. The virus was found by PCR in 6 (1%) of 637 nasopharyngeal aspirates and in 1 (0.5%) of 192 fecal samples but was not detected in sets of urine and blood samples^ref. When 951 respiratory samples collected in Queensland, Australia, between November 2002 and August 2003 from patients with respiratory infection, were tested for the presence of the KI virus, 24 (2.5%) samples were positive for KI virus with 20 (83%) of these from children younger than 5 years. In 6 (25%) patients KI was co-detected with another virus. Full genome sequencing of three isolates shows a high degree of conservation between the Queensland isolates and the original isolates reported from Swedish patients^ref
• WU Polyomavirus : initially detected in a nasopharyngeal aspirate from a 3-year-old child from Australia diagnosed with pneumonia. Screening of 2,135 patients with acute respiratory tract infections in Brisbane, Queensland, Australia, and St. Louis, Missouri, United States, using WU virus-specific PCR primers resulted in the detection of 43 additional specimens that contained WU virus^ref
• Merkel cell polyomavirus (MCV) was identified in Merkel cell carcinomas (MCC) using digital transcriptome subtraction (Feng et al., 2008).
• Poxviridae: the poxviruses: a family of DNA viruses having a brick-shaped or ovoid virion 220–450 x 140–260 nm consisting of an envelope containing lipid and tubular or globular protein structures surrounding a DNA-containing core and one or two lateral bodies. The genome consists of a single molecule of double-stranded DNA (size 130–375 kbp). Viruses contain over 100 proteins; some are ether-resistant while others are ether-sensitive. Replication and assembly occur in the cytoplasm; virions are released by cell destruction or budding. Host range is narrow and transmission is by fomites, airborne particles, arthropod vectors, or contact. There are 2 subfamilies :
• Entomopoxvirinae (which includes 3 genera of poxviruses infecting invertebrates)
• Chordopoxvirinae (poxviruses of vertebrates, causing zoonoses^ref)
• Avipoxvirus
• fowlpox virus
=> Bollinger bodies
• Capripoxvirus comprising the sheeppox, goatpox, and lumpy skin disease viruses.
• Leporipoxvirus infect squirrels and rabbits, including myxoma virus and rabbit fibroma virus.
=> T2 proteins are TNFRII-like decoys
• Molluscipoxvirus
• Molluscum contagiosum virus (MCV)
• Molluscum contagiosum virus subtype 1
• Molluscum contagiosum virus subtype 2
• Molluscum contagiosum virus subtype 3
Epidemiology : it occurs worldwide, but is much more frequent in certain areas like Zaire and Papua New Guinea. It is seen most commonly in children
Proteomics : binding of FADD and caspase-8 to MC159 v-FLIP (which inhibits Fas-, TNF-, and TRAIL-induced apoptosis) is not sufficient for its antiapoptotic function
Transmission : direct bodily contact, through minor abrasions, or indirectly via fomites (swimming pools, ...) : among young adults, it is usually a STD.
Proteomics :
• MC148, a CCR8-like decoy receptor
Large hyaline acidophilic granular masses known as Henderson-Peterson's bodies / molluscum bodies fill the cytoplasm and push the nucleus to the edge of the infected cells.
=> molluscum contagiosum
• Orthopoxvirus (OPV)
• Aracatuba virus (a.k.a. Araçatuba virus)
Epidemiology : Minas Gerais state, Brazil
=> cowpoxlike outbreak in a dairy herd (nodular and pustular lesions on bovine teats, frequently related to viral infections such as bovine herpes mammillitis, pseudocowpox, and cowpox infections) and a related case of human infection in hand of dairy farm worker (milker). Diagnosis was based on virus growth characteristics, electron microscopy, and molecular biology techniques. Molecular characterization of the virus was done by using polymerase chain reaction amplification, cloning, and DNA sequencing of conserved orthopoxvirus genes such as the vaccinia growth factor (VGF), thymidine kinase (TK), and hemagglutinin. Gene sequences showed 99% homology with vaccinia virus genes and were clustered together with the isolated virus in the phylogenetic tree. Aracatuba virus is very similar to Cantagalo virus (could represent its spread), showing the same signature deletion in the gene^ref
• Camelpox virus (CMLV)
Epidemiology :
Genomics : among OPVs, CMLV is the most closely related to variola virus (96% amino acid identity), sharing all genes involved in basic replicative functions and the majority of genes involved in other host-related functions. 27 CMLV ORFs are absent in variola virus, including 7 full-length homologues of NMDA-like receptor, PL-D, Schlafen, MT-4 virulence, kelch, vaccinia virus C8L, and cowpox virus B21R proteins. 38 CMLV ORFs, some of which are fragments of larger genes, differ in size from corresponding VARV ORFs by more than 10% (amino acids). As it has been suggested for VARV, it may have originated from a cowpox virus-like ancestor.
=> camelpox, a disease which exclusively affects Camelidae: clinical manifestations vary from a singular pox lesion to a generalized form, with pox literally covering the entire animal and even found on internal organs (e.g. lungs)
Prognosis : mortality may reach 30%, and complications due to secondary bacterial and mycotic infections are common. Severe cases of camelpox to the point of fatality have been described in camels from Saudi Arabia after they have been exported to the UAE^ref.
Differential diagnoses include: 1. papillomatosis, the warts of which may be taken as pox lesions after secondary bacterial infection, but they are usually smaller, and 2. contagious ecthyma caused by Pseudocowpox virus, a member of the genus Parapoxvirus. Pox induced through an infection with the latter cannot be clinically distinguished from pox caused by camelpoxvirus. Lumpy skin disease (LSD, caused by another poxvirus which belongs to another genus, Capripoxvirus, with the better-known members Sheeppox virus and Goatpox virus) has not been described on the Arabian peninsula yet  Until 1988, it was restricted to sub-saharan Africa, but it is now known in Egypt^ref. LSD does infect cattle and displays a clinical picture resembling pox, but the host range does not include camels. On the other hand, the host range of camelpox is restricted to Old World camelids (New World camelids are susceptible to the infection, but the natural occurrence of camelpox is restricted to the Old World - with the exception of Australia). Hence, camelpox is unlikely to be the cause of the observed disease in cows. To cut this short; if the described pox-like disease in camels and cows is indeed caused by the same etiological agent, pseudocowpox virus would be a possible but very surprising candidate, because -- at least in cows -- only the udder is usually affected and fatal outcomes are very unusual. Hence, it seems more likely that 2 different viruses are at work: one causing the pox in camel and the other responsible for the effects seen in cattle. Alternatively, bacterial infection(s) might also be considered. LSD has been recorded and reported in Bahrein (1993, 1994, 2002, 2003); Kuwait (1991); Oman (1994); and the United Arab Emirates (2000). These might have been introductions from Eastern Africa by imported cattle for slaughter^ref.
• Cantagalo virus (CTGV)
Epidemiology : isolated from skin lesions on dairy cows and milkers during recent exanthem episodes in Cantagalo County, Rio de Janeiro State, Brazil. It is more like vaccinia virus (VV) than cowpox virus. An eruptive moderate form of camelpox^ref. CTGV may have derived from VV-IOC by persisting in an indigenous animal(s), accumulating polymorphisms, and now emerging in cattle and milkers as CTGV. CTGV may represent the first case of long-term persistence of vaccinia in the New World^ref
• Cowpox virus (CWXV / CPXV))
• Cowpox virus (strain Turkmenia-1974)
• Cowpox virus (strain Hamburg-1985)
Epidemiology : found only in Europe and in adjacent parts of the former USSR. Despite its name, the reservoir hosts of cowpox virus are Rodentia, from which it can occasionally spread to Felis catus, Canis familiaris, Bos taurus, and zoo animals, including large cats and elephants.
Transmission to humans has traditionally occurred via contact with the infected teats of milking cows : however, currently, infection is seen more commonly among domestic cats.
Proteomics :
• cytokine response modifying (Crm) proteins
• crmA inhibits the activation of caspases 1 and 8 and prevents IL-1b and IL-18 processing
• crmB is a p48 secreted p75^TNFRII-like decoy receptor for TNF-a and TNF-b
=> cowpox : 9-10 days incubation => pustules at the site of their introduction into the skin (usually the hands: on the thumbs, the first interdigital cleft, and the forefinger), rarely fever and myalgia => secondary lesions occur only in individuals with immunological deficiencies.
Pathogenesis : greater epithelial thickening, less rapid cell necrosis, and more involvement of the mesodermal tissues than with variola virus
Therapy : VIG should be restricted to the most severe cases. Usually, the lesions regress spontaneously.
ectromelia virus (EV)

Proteomics :
• soluble, secreted receptors for IFN-g and IFN-a/b that are homologous to those identified in other OPVs : anyway vIFN-a/bR is unable to inhibit mouse IFN-b.
• dsRNA-binding protein encoded by an intact homolog of the VV E3L gene.
• no functional K3L gene, which encodes a viral eIF-2a homolog
=> mousepox / infectious ectromelia : a lethal disease of mice characterized by gangrene and often loss of one or more of the feet and sometimes of other external parts, and by necrotic areas in the liver, spleen, and other organs. Introduction of the T_h2cytokineIL-4 gene in ectromelia virus further increases lethality, even in recently immunized genetically resistant mice. These data therefore suggest that virus-encoded IL-4 not only suppresses primary antiviral CMI but also can inhibit the expression of immune memory responses.
monkeypox virus (MPXV)
• Monkeypox virus (strain Sierra Leone 70-0266)
• Monkeypox virus (strain Zaire 77-0666)
Epidemiology : found only in the small villages of the tropical rain forests of western and central Africa, with cases mostly reported in Zaire : only 400 cases were reported worldwide from the time infection by monkeypox virus was first observed in 1970 (in the Democratic Republic of the Congo (DRC) in a region where smallpox had been eradicated in 1968) to 1986.
• Sudan^ref : from 27 Oct 2005 until 18 Nov 2005, 19 cases in Bentiu, Unity State; related to the DRC clade^ref
• Democratic Republic of the Congo (DRC)
• an outbreak of human monkeypox in the between February 1996 and October 1997 was associated with person-to-person transmission; a change from prior limited outbreaks. Previous studies over a 20-year period had shown that the rate of transmission of monkeypox within households was low, suggesting that the disease had a low potential for transmission from person to person. Outbreaks were generally self-limiting after 1-2 sequential transmissions. The percentage of suspect cases from person-to-person transmission (78%) was higher in this outbreak than previously reported (30%) and the proportion of patients that were > 15 years (27%) was higher than previously reported (8%). This was associated with the clustering of cases in household compounds and prolonged chains of transmission from person to person.
• a human monkeypox epidemics in Impfondo (a remote, isolated town of approximately 45 000 people in the center of the Congo Basin Rain Forest, capital of the Likouala Region, which is the northernmost region of the Democratic Republic of Congo (DRC). Impfondo is located on the western banks of the Oubangui River, a major tributary of the Congo River) initiated on 15 Apr 2003 was then discovered on 14 June.
• a monkeypox virus epidemic has been reported near Mbuji Mayi (which is located in the South-Central region of the country). 56 people from Kanama in the Kabinda District, which include 14 children aged < 5 years and 2 of other age groups, have been treated at the Kanama health center, but no deaths have been reported.
• Kasai Occidental province : several people suffered from monkeypox during Aug-Oct 2006 in Kananga ^ref
• USA : since May 16 to July 8 2003, 71 possible cases (35 laboratory-confirmed) have been reported  :
• 39 in Wisconsin (14 laboratory-confirmed in people as young as 4 and as old as 48)
• 16 in Indiana (7 laboratory-confirmed)
• 12 in Illinois (8 laboratory-confirmed)
• 2 in Missouri (laboratory-confirmed)
• 1 in Ohio
• 1 in Kansas (laboratory-confirmed)
The median age was 28 years (range: 1 to 51 years). The outbreak has been caused by to Utah prairie dogs (Cynomys parvidens) sold from a suburban pet distributor (Phil's Pocket Pets) in Villa Park, Chicago, Illinois, USA. That distributor had a giant Gambian rat (Cricetomys emini), indigenous to African countries, that may have infected batches of prairie dogs. Of the 50 Gambian rats (among > 800 small mammals of 9 different species, including 6 genera of African Rodentia : rope squirrels (Funisciurus spp.), sun or tree squirrels, (Heliosciurus spp.), Gambian giant rats, brushtail porcupines (Atherurus spp.), dormice (Graphiurus spp.), and striped mice (Hybomys spp.)) imported from Ghana in the early April shipment, 10 died en route to the Texas distributor or shortly after arrival, one died later at the distributor's premises, 5 were shipped to a pet store within Texas, 9 remain alive at the distributor's premises, and from 18 to 25 of the rats were sent to Evelee Prokes, owner of the Menagerie Hill Farm in Cincinnati, Iowa, with 18 of those sent from Iowa to the Illinois dealer. The shipment contained approximately 800 small mammals of 9 different species that might have been the actual source of introduction of monkeypox. Of the 5 sold to the pet store in Texas, one was sold to an individual. Authorities said the animal and the owner are fine. The other 4 died. Officials said it is not unusual for deaths to occur in wild animals brought into captivity and that the deaths cannot be assumed to have been caused by monkeypox. TDH officials are hopeful that testing of the live Gambian rats remaining at the distributor's premises and of a dead Gambian rat from the pet store that had been kept frozen may offer additional clues in the ongoing multi-state investigation. Texas officials also said that while the prairie dogs sold by the dealer in Illinois are believed to have come from a Texas distributor, it is not the same dealer who supplied the Gambian rats. They said it does not appear that the prairie dogs and Gambian rats were ever in the same facility in Texas. All patients have had contact with animals; however, at least 2 patients also reported contact with another patient's lesions or ocular drainage. A total of 51 patients reported direct or close contact with prairie dogs, and 1 patient reported contact with a Gambian giant rat. One patient had contact with a Oryctolagus cuniculus that became ill after exposure to an ill prairie dog at a veterinary clinic. No patients have died and 26% patients have been hospitalized, including a child aged <10 years with encephalitis (requiring hospitalization for 14 days) and second child exposed to 3 ill prairie dogs, hospitalized with profound painful cervical and tonsillar adenopathy and diffuse pox lesions, including lesions in the oropharynx. Although the child had difficulty breathing and swallowing, mechanical ventilation was not required. The date of onset for the last case was 20 Jun 2003^ref. Studies indicate that West African and Congo basin isolates of monkeypox virus (MPXV) are genetically distinct. Congo basin MPXV-ZAI-V79 is more virulent for cynomolgus monkeys as compared to presumed West African MPXV-COP-58. This finding may explain the lack of case-fatalities in the U.S. 2003 monkeypox outbreak, which was caused by a West African virus. Virulence differences between West African and Congo basin MPXV are further supported by epidemiological analyses that observed a similar prevalence of antibodies in non-vaccinated humans in both regions, while > 90% of reported cases occurred in the Congo basin, and no fatal cases were observed outside of this region. To determine the basis for this difference in virulence, the genomes of one human West African isolate, and 2 presumed West African isolates were sequenced and compared the sequences to Congo basin MPXV-ZAI-96-I-16. The analysis identified D10L, D14L, B10R, B14R, and B19R as possible virulence genes, with D14L (ortholog of vaccinia complement protein) as a leading candidate^ref. Unpublished experiments Army researchers had done in the 1990s on such viruses in monkeys as part of an effort to find ways to test new smallpox vaccines showed monkeys infected with the West African strain got only mildly ill and none died. 5 out of 6 of those given the other strain got severely ill and all 3 that got the higher dose of it died.
Genomics : 15 genes are carried by smallpox but not by monkeypox. Determination of the complete sequence of the genome of monkeypox virus, however, has indicated that monkeypox virus lacks some of the immunomodulatory genes possessed by smallpox virus, which suggests that monkeypox virus is unlikely to become endemic in the human population. The probability of monkeypox virus mutating into variola virus is likely to be remote.
Transmission : a rare zooanthroponosis from monkeys (which are affected only by mild, epidemic exanthematous disease) and some Rodentia (African tree squirrels (Heliosciurus and rope squirrel (Funisciurus anerythrus)), degu (Octodon degus), Oryctolagus cuniculus) via small lesions on the skin or oral mucous membranes. Person-to-person transmission by respiratory route accounts for < 33% of observed cases : this makes identification and containment much more accessible and the secondary attack rate is low. Nonetheless, the fear has been expressed that monkeypox might evolve to become an endemic human infection
=> monkeypox : 1-31 days (median : 12 days) incubation => features are almost indistinguishable from those of ordinary-type smallpox (generalized pustular rash, fever, and toxemia) with the exception of a greater degree of cervical and inguinal lymphadenitis(47%), including fever preceding or accompanying the onset of a generalized papular rash on the head, trunk, and extremities (73%; typically progressing through stages of vesiculation, pustule, umbilication, and encrustation. Early lesions become ulcers in some patients : many patients had initial and satellite lesions on palms, soles, and extremities. Rashes are generalized in some patients); respiratory symptoms (64%), lymphadenitis , and sore throat (33%). The virus first localizes in mononuclear phagocytic cells, is released into the bloodstream, and then localizes again in skin cells. It also has a healing period that progresses more rapidly than smallpox, but anyway still significant morbidity and mortality (1-10%, with the highest rates among young children).
Laboratory examinations :
• the clinical diagnosis of monkeypox is not so easy, and chickenpox can be mistaken for monkeypox. Moreover, varicella (chickenpox), which is considered as an ordinary mild disease, can wear a very different clinical aspect and even be a fatal disease for an immunodepressed organism. In DRC, the prevalence rate of HIV is quite high
• real-time PCR^ref
Prevention : attenuated vaccine has 85% prevention rate
Therapy : the effectiveness of (1) post-exposure smallpox vaccination and (2) antiviral treatment with either cidofovir or with a related acyclic nucleoside phosphonate analogue (HPMPO–DAPy) were compared after lethal intratracheal infection of cynomolgus monkeys (Macaca fascicularis) with monkeypox virus (MPXV). Initiation of antiviral treatment 24 h after lethal intratracheal MPXV infection, using either of the antiviral agents and applying various systemic treatment regimens, resulted in significantly reduced mortality and reduced numbers of cutaneous monkeypox lesions. In contrast, when monkeys were vaccinated 24 h after MPXV infection, using a standard human dose of a currently recommended smallpox vaccine (Elstree-RIVM), no significant reduction in mortality was observed. When antiviral therapy was terminated 13 days after infection, all surviving animals had virus-specific serum antibodies and antiviral T lymphocytes^ref.
• Vaccinia virus (VACV)
• Vaccinia virus (strain Ankara)

Used as transfection vector.
• Vaccinia virus (strain Copenhagen)
• Vaccinia virus (strain Dairen I)
• Vaccinia virus (strain IHD-J)
• Vaccinia virus (strain L-IPV)
• Vaccinia virus (strain LC16M8)
• Vaccinia virus (strain LC16MO)
• Vaccinia virus (strain Lister)
• Vaccinia virus (strain LIVP)
• Vaccinia virus (strain Tian Tan)
• Vaccinia virus (strain WR 65-16)
• Vaccinia virus (strain Western Reserve (WR))
=> a 40-year-old Caucasian male who had been vaccinated against smallpox at 1 year old and again when 10 years old developed vesicles that gradually turned into raised, dark nodules (as similar to those that develop during cowpox infection) on a finger on each hand after working in lab with very high concentrations of recombinant WR containing an inactivated form of the human gene for cytohesin-1, which could impair the local immune response in the skin by interfering with leukocyte adhesion^ref
• Vaccinia virus (strain Wyeth)
Epidemiology : since 1999, an increasing number of exanthemous outbreaks affecting dairy cattle and cow milkers in Brazil have been reported (Araçatuba virus^ref, Cantagalo virus^{ref, ref}). Since 1963, all Brazilian orthopoxvirus isolates have been characterized as VACV strains^{ref1, ref2, ref3, ref4}. The growing geographic distribution of these outbreaks indicates that these viruses may be emerging as zoonotic pathogens of cattle. This fact is especially important because a growing human population has no vaccine-derived immunity to smallpox or other orthopoxviruses. This situation could create an opportunity for these viruses to disseminate in Brazil. In addition, the isolation of another VACV strain (Passatempo virus) during an outbreak that emerged in March 2003 in the town of Passa-Tempo, Minas Gerais State, Brazil, strengthens the hypothesis that VACV is circulating in the New World and that these viruses seem to be endemic of this region^ref.
It is not known whether vaccinia virus is the product of genetic recombination, or if it is a species derived from buffalopox virus > cowpox virus or camelpox virus or variola virus by prolonged serial passage, or if it is the living representative of a now extinct virus (horsepox).
Proteomics :
• A44L is a 3b-hydroxysteroid dehydrogenase (3b-HSD) which promotes corticosterone synthesis leading to immunosuppression
• A46R and A52R block TLRs and IL-1R signal transduction.
• B1R kinase is ortholog to human Vaccinia related kinase 1 (VRK1), VRK2, and VRK3
• E3L inhibits PKR
• SalF2R encodes a protein related to C-type animal lectins
• SalF7L encodes an active 3b-hydroxysteroid dehydrogenase
• SalF17R
• SalF16R encodes a TNFR
• Vaccinia-virus complement-regulator protein (VCP) is a co-factor for factor I-mediated degradation of both C3b and C4b.
• VH1 phosphatase is ortholog to human DUSP1, DUSP3, and DUSP8.
• thymidylate kinase
• VHR, a Vaccinia virus VH1-related dual-specific protein phosphatase, is phosphorylated at Y138 by ZAP-70.
• DNA ligase
• profilin
• SOD
• part of guanylate kinase
• 2 vaccinia virus genes encoding glycoproteins of the outer envelope of extracellular enveloped virus are conserved in variola virus and this homology is likely to have contributed to the immunological protection which vaccinia virus evoked against smallpox.
Grb2 and Nck1 act cooperatively to promote actin-based motility of vaccinia virus
=> no natural host known
=> 40-60% of infected mice develop viremia and die : with IL-4 gene added the mortality is 100%.
Attenuated strains are used for anti-Orthopoxvirus vaccine.
• Variola virus (VARV)
A comparison of the sequences of 21 different poxviruses revealed the 90 essential genes that equip the viruses to infect and multiply in cells^ref.
Prevention : variolation => anti-Orthopoxvirus attenuated vaccine
Therapy : cidofovir
• Parapoxvirus
• Auzdyk disease virus [camels & sheep?]
• bovine papular stomatitis virus

=> papular stomatitis : a zooanthroponosis (reservoir : Bos taurus)^{ref1, ref2}
• camel contagious ecthyma
• Chamois contagious ecthyma virus
• orf virus / contagious pustular dermatitis virus / ecthyma contagiosum virus
Epidemiology : worldwide, most common in late summer, fall, and winter on pasture, and in winter in feedlots
Pathogenesis^ref
Transmission : a zooanthroponosis through contact with infected reservoir (Ovis aries, Capra hircus, Ovibos moschatus moschatus, Rangifer tarandus, Rupicapra rupicapra, deer^ref) ; indirect infections through contaminated knives or meat have been reported. Transmission of orf virus to humans occurs after contact with infected or recently vaccinated animals and/or fomites in conjunction with skin trauma. Orf virus vaccine strains have been known to cause outbreaks among sheep^ref, and 3 of the illnesses described in this report occurred soon after vaccination of the flock. Veterinary vaccines for orf virus use non-attenuated, live virus preparations and are intended to produce controlled infections in flocks (De la Concha-Bermejillo A, Ermel RW, Zhang MZ, Guo J. Contagious ecthyma (orf) virulence factors and vaccine failure. In: Proceedings of the United States Animal Health Association; Richmond, VA: United States Animal Health Association; 1999). Recently vaccinated animals pose an occupational risk to humans^ref. Orf virus infection is facilitated by skin trauma^ref, and previous case series have associated skin trauma with orf virus infection^ref. Trivial injury (e.g., pricks from thistle) or substantial trauma (e.g., bites) can facilitate transmission of orf virus. Therefore, barrier protection (e.g., nonporous gloves) and hand washing during the care of sheep and goats is recommended whenever feasible. These measures are especially important for any person with a compromised immune system or a chronic skin disorder (e.g., eczema) who has contact with overtly infected animals. Immunocompromised persons should discuss the risks of handling orf-infected animals and infection-prevention strategies with their primary-care physicians. Human orf virus infection is a common yet preventable consequence of contact with sheep and goats. Persons who are most likely to be exposed to orf virus (e.g., farm workers) might be familiar with the infection and thus might not seek medical attention. As a result, clinicians might not be familiar with orf virus infections, leading to a delay in diagnosis and unnecessary antibiotic use. Public health personnel should be cognizant that orf virus infection is similar in appearance and risk factors to life-threatening infections such as cutaneous anthrax and that skin trauma is a predisposing factor to infection.
=> in reservoirs (scabby or sore mouth / contagious ecthyma or pustular dermatitis / orf) : erythematous vesiculopustular eruption on-wool-bearing areas, especially the lips and oral mucosa of young animals, the lesions of which may coalesce and crust over. The proliferative lesions may occasionally occur on the teats and, more seldom on the coronary bands of the feet of sheep and goats. During the course of the disease (1-4 wks), the scabs drop off and the tissues heal without scarring. During active stages of the infection, the more severely affected lambs fail to eat normally and lose condition. Extensive lesions on the feet lead to lameness. Mastitis may result in ewes with lesions on the udder.
=> in humans (occasionally affected) : orf / contagious pustular dermatitis / ecthyma contagiosum.
Differential diagnosis : resemble skin lesions associated with potentially life-threatening zoonotic infections such as tularemia, cutaneous anthrax, and erysipeloid (CDC. Human orf mimicking cutaneous anthrax---California. MMWR 1973;22:108); therefore, rapid and definitive diagnosis is critical. Tularemia and erysipeloid are generally associated with exposure to rabbits or New World sylvan rodents and swine, respectively. Both orf virus infection and naturally acquired anthrax in humans can result from exposure to domestic sheep and goats; thus, exposure history alone (i.e., animal contact) is insufficient to indicate etiology, necessitating laboratory evaluation. Histopathologic features include intraepithelial ballooning and intracytoplasmic inclusions^ref; however, these findings are suggestive and not pathognomonic. Negative-stain electron microscopy can confirm a parapoxvirus infection by demonstrating classic ovoid cross-hatched virions but cannot distinguish orf virus from other parapoxviruses such as paravaccinia (pseudocowpox) virus; serologic testing has the same limitation. Only PCR can definitively identify a parapoxvirus as orf virus. 2 assays have been used by CDC: standard PCR^ref and real-time PCR, which is nearly 1000 times more sensitive^ref. These assays are ideally performed on frozen tissue specimens, vesicle material, or scab debris.
Therapy : self-limiting in hosts with normal immune systems, while immunocompromised patients can have progressive, destructive lesions requiring medical interventions such as cidofovir^ref and surgical debridement^ref.
• pseudocowpox virus / paravaccinia virus / milker's nodule virus (MNV)

=> nodular lesions similar to those of cowpox and orf on the udders and teats of milk cows and the oral mucosa of suckling calves
=> milker's nodule : a zooanthroponosis (reservoir : Bos taurus during milking
• sealpox virus

Transmission : ^ref, captive grey seals (Halichoerus grypus)^ref
• Suipoxvirus
• swinepox virus (SWPV)

Genomics :
• IFN-g receptor
• IFN resistance protein
• IL-18 binding protein
• IFN-a/b binding protein
• extracellular enveloped virus host range protein
• dUTPase
• hydroxysteroid dehydrogenase
• SOD
• serpin
• herpesvirus MHC inhibitor
• ectromelia virus macrophage host range protein
• myxoma virus M011L
• variola virus B22R
• 4 ankyrin repeat proteins
• 3 kelch-like proteins
• 5 vaccinia virus (VV) A52R-like family proteins
• 2 GPCRs
=> swinepox.
• Yatapoxvirus
• Tanapox virus (TPV)
First seen among individuals in the flood plain of the Tana River in Kenya during 2 epidemics (1957 and 1962) of acute febrile illness accompanied by localized skin lesions. Human tanapox has been mostly documented in Kenya and Zaire, but it is believed to occur much more widely throughout tropical Africa.
=> tanapox (most likely a zoonosis transmitted from monkeys or another reservoir host  by infected arthropods; only 1 case of human to human transmission has been reported) : fever during 3-4 days incubation => severe headache and backaches, itching erythema with central thickening of the prickle cell layer => papule which gradually enlarges to reach a maximum Ø of ~ 15 mm by the end of the second week of infection (regional lymphadenitis from about the 5^th day following the appearance of the skin lesion) => ulcers during the third week => gradually heals within 5 to 6 weeks, leaving a scar. In Kenya, the lesions were almost always solitary and were found on the upper arm, face, neck, and truck ; conversely, in Zaire, 22% of patients had multiple lesions (usually 2 or 3, maximum 10), mostly found on the lower limbs, with a couple of patients reporting lesions on the upper limbs, trunk, and head. The virus is much slower in replication than vaccinia virus, with most of the mature progeny is retained inside the cell.
Laboratory examinations :
• laboratory tests not capable of discriminating smallpox from vaccinia, monkeypox, or cowpox
• TEM
• light microscopy after H&E staining^ref :
• A-type inclusion bodies
• B-type inclusion bodies / Guarnieri's bodies or corpuscles
• gel diffusion test : vesicular fluid from a pox lesion incubated with vaccinia hyperimmune serum, constitutes a rapid and inexpensive method when microscopy is not available^ref
• antiorthopoxvirus IgM
• differentiation among orthopoxviruses
• isolation of the virus and characterization of its growth on chorioallantoic membrane of 10- to 12-day-old chick embryos. Pocks produced by smallpox are small and grayish white, whereas those for vaccinia are larger and sometimes hemorrhagic. Variola minor exhibited greater temperature sensitivity on chorioallantoic membranes than did variola major
• real-time PCR
Web resources : Poxvirus Bioinformatic Resource Center
• Mimivirus (misnomer : Mimi) is an unclassified dsDNA icosahedral, not filterable and not enveloped virus, with no RNA stage, discovered in 1992, nestling inside an amoeba found inside a cooling tower in Bradford, UK, that was being investigated as the source of an influenza outbreak. Mimivirus defines a new class of nucleocytoplasmic large DNA virus (NCLDV). It measures about 800 nm across, > 4 times as big as a smallpox virus^ref. Mimivirus has a single  circular genome of approximately 1.2 million bases, which is more than many bacteria contain and makes it several times bigger than the largest DNA viruses. > 90% of its DNA does something specific : the bases make up 1,260 genes, which makes it as complex as some bacteria. Mimi carries about 50 genes that do things never seen before in a virus. It can make about 150 of its own proteins, along with chemical chaperones to help the proteins to fold in the right way. It can even repair its own DNA if it gets damaged, unlike normal viruses. And although viruses can use either DNA or RNA to carry their genetic information, Mimi has both. As Mimi carries some genes involved with replication, this could have helped it to spread faster than other viruses. Officially, the virus got its name because it mimics bacteria, but Raoult's father, also a scientist, taught me a story about Mimi the Amoeba when the discoverer was very young, so it's also a tribute to him. Some scientists have speculated that eukaryotes originally evolved from collaboration between a virus and a bacterium. Bacteria could have supplied the ribosomes, the protein factories of the cell, and viruses might have injected their genetic material into a proto-nucleus. One weakness of the theory is that viruses generally lack some of the key genes seen in eukaryotes. But Mimi's complex genome includes these, lending support to the idea^ref. It is a putative human pathogen : serologic evidence of infection was observed in 20% of ICU patients with pneumonia^ref
• ssDNA viruses
• Anellovirus
• Torque Teno virus (TTV) (a.ka.. TT virus, where TT stands for the initials of the Japanese patient in which it was first isolated by PCR in 1997; nowadays the acronym has been readapted as "transfusion transmitted"). TTV was the first human virus with a single stranded circular DNA genome. TTV was considered to be a member of Circoviridae, but others suggested it conformed to a new family. TTV is distinct from ambisense viruses in the genus Circovirus, since the former genome is negative stranded. The genome structure of TTV is more related to chicken anaemia virus in the genus Gyrovirus, however, the sequence similarity is minimal except for a short stretch at 3816-3851 of TA278.
Genomics : the virus is heterogenous; 16 different genotypes are currently registered, and it can be classified as a "swarm" of at least 5 different viruses.
Epidemiology : depending on the PCR technique used, the prevalence of infection ranges from 1.9 to 36% among blood donors, from 11.5 to 71% in hemodialysis patients, from 47 to 82% among patients with non-A, non-B or non-C fulminant hepatic failure, and the most elevated percentage is found in hemophiliacs. PCR standardization is needed to clearly establish its real prevalence worldwide.
Transmission : epidemiological studies have established that the routes of TTV infection might be parenteral, oral-fecal, and possibly salivary. TTVs are prevalent in non-human primates and human TTV can cross-infect chimpanzees. Furthermore, TTV sequences have been detected in chickens, pigs, cows and sheep. TTV can be transmitted by mother-to-child infection. However, within a year after birth, the prevalence reaches the same level for children born to both TTV-positive and TTV-negative mothers even without breast-feeding.
Pathogenesis : due to the lack of suitable cell systems to support the growth of TTV, the biology of TTV is still obscure. The non-coding region surrounding a short 113 nt GC-rich stretch and occupying approximately one-third of the genome is considered to contain the putative replication origin. 3 mRNAs are expressed by TTV, 3.0 and 1.2 and 1.0 kb species. A protein translated from the 3.0 kb mRNA is considered to be the major capsid protein as well as replicase. The nature of the proteins translated by the other 2 mRNAs are still putative^ref.
=> usually commensal. Its widespread presence in the blood of infected subjects contrasts with the apparent absence of pathological symptoms.
=> non-A, non-G post-transfusional acute hepatitis. TTV may play a role in the pathogenesis of non-A, non-B or non-C fulminant hepatic failure. Patients co-infected with hepatitis C virus (HCV) and TTV have a significantly higher histological grade score than patients with isolated HCV infection
=> might be a contributing factor in liver damage in children^ref and in the lung impairment caused by asthma^ref.
=> in 239 TTV⁺ people, multiple-genogroup infections were common and associated with higher viral loads than would be expected from simple additive effects. The latter observation was restricted to the infections which included both genogroups 1 and 3, pointing to the possible existence of some kind of infection facilitation between these genogroups^ref.
Treatment with IFN seems to decrease TT viremia, according to results obtained outside the context of clinical trials^ref
unclassified Anellovirus
• small anellovirus (SAV) (identified in 2006) is present in the blood of healthy persons (20% prevalence), and also in their PBMNC and saliva samples^{ref1, ref2}
• Small anellovirus 1
• Small anellovirus 2
• Small anellovirus BEC-VIPI
• Small anellovirus DF-VIPI
• Small anellovirus DT-VIPI
• Small anellovirus FIL-VIPI
• Small anellovirus GAR-VIPI
• Small anellovirus GIAN-VIPI
• Small anellovirus KR-BD
• Small anellovirus RIC-VIPI
• Small anellovirus TER-VIPI
• TTV-like mini virus (TTMV) (identified in 2000)^{ref1, ref2, ref3, ref4, ref5, ref6, ref7, ref8, ref9}

Epidemiology : 72% of healthy Brazilian blood donors were TLMV DNA positive^ref
Transmission : mother-to-neonatal intrauterine transmission or transmission via breast milk may^ref; adults and children are coinfected frequently with several TLMV isolates of different origins^ref
Pathogenesis : in a few cases, episodes of a considerable increase in viraemia were observed, but in most patients there were no discernible increases as immune deficiency progressed^ref. In patients receiving immunosuppressants subsequent to kidney transplantation, viral titers tended to increase; in soldiers undergoing extreme training known to cause immunosuppression, insignificant increases in titers were observed; and IFN treatment of patients with HCV caused a temporary decrease in TTV and TLMV titers^ref.
• Circoviridae
• unclassified Gyrovirus
• Human gyrovirus type 1 (HGyV)

• Parvoviridae: the parvoviruses: a family of DNA viruses having a nonenveloped virion 18–26 nm in diameter composed of 60 copies of the capsid protein with icosahedral symmetry. The genome consists of a single molecule of linear single-stranded DNA (MW 1.5–2.2 ´ 10⁶, size 4–6 kb). Viruses contain 2–4 major polypeptides, depending on the species, and are resistant to heat, lipid solvents, deoxycholate, and nucleases but sensitive to formalin, b-propiolactone, hydroxylamine, oxidizing agents, and ultraviolet radiation. Replication and assembly occur in the nucleus and require S-phase cellular function in the host cell or the presence of helper virus. Host range is narrow and transmission may be vertical or by mechanical vectors. Canine parvovirus (CPV) is an emerging DNA virus that was first observed to cause disease in canines in 1978 and has since become a ubiquitous pathogen worldwide. CPV emerged from feline panleukopenia parvovirus (FPLV) or a closely related virus, differing at several key amino acid residues. Although FPLV has remained an endemic infection in its host populations, since the 1970s, the newly emerged CPV has undergone an epidemic-like pattern of logistic/exponential growth, effectively doubling its population size every few years. This rapid population growth was associated with a lineage of CPV that acquired a broader host range and greater infectivity. Recombination played no role in the emergence of CPV. Rather, any preexisting variation in the donor species and the subsequent rapid adaptation of the virus to canines were likely dependent on a high rate of mutation and the positive selection of mutations in the major capsid gene. Strikingly, although these single-stranded viruses have a DNA genome and use cellular replication machinery, their rate of nucleotide substitution is closer to that of RNA viruses than to that of double-stranded DNA viruses^ref. There are 2 subclasses:
• Densovirinae, comprising genera that infect invertebrates
• Parvovirinae, comprising 5 genera that infect vertebrates (mammals and birds). Viruses multiply in the nucleus and require S-phase cellular functions for replication. Transmission is transplacental or by mechanical vector. Human parvoviruses cause transient aplastic crisis, acute arthritis, erythema infectiosum, hydrops fetalis, spontaneous abortion, and fetal death. Animal pathogens include bovine, canine, feline, and goose parvoviruses, feline panleukopenia virus, mink enteritis virus, Aleutian mink disease virus, and various murine parvoviruses.
• human parvovirus RA-1 : a species belonging to the genus Parvovirus that has been associated with rheumatoid arthritis
• Amdovirus
• Bocavirus comprise 3 species
• unclassified Bocavirus
• human bocavirus (HBoV) : in 2001, 2 previously unknown parvoviruses were discovered in bovine sera used as diluent. These 2 novel parvoviruses proved to be frequent contaminants of bovine sera^ref. Among the detected viruses were one coronavirus and one parvovirus, both of which were at that time uncharacterized. The parvovirus was in a retrospective clinical study detected in 17 additional patients and associated with lower respiratory tract infections in children^ref. In a 2nd study, Janice Louie of the California Department of Health Services, Lawrence Drew of the University of California, San Francisco and colleagues checked patients reporting to the hospital with flu-like illness including "unspecified upper respiratory infection," acute bronchitis, sinus infections, and pneumonia. They could identify a virus in only 39% of the patients. These included influenza A or B in 54 patients, picornavirus in 28, RSV in 12, human metapneumovirus in four and human coronavirus OC43 in 2 patients^ref. Subsequent to publication of these papers, others have found that HBoV is frequently found in nasopharyngeal samples of hospitalized infants and children with acute respiratory tract diseases. Proving the clinical relevance of HBoV is challenging, because application of some of Koch's revised postulates is not possible. Because of the high rate of coinfections with HBoV and other respiratory tract pathogens, an association between HBoV and respiratory tract diseases remains unproven. For example, a Brisbane study^ref made an additional 206 viral detections, resulting in the identification of a virus in 67.0% of specimens. The majority of the infectious agents were RNA viruses (89.9%). Overall, human rhinoviruses (HRVs) were the most frequently identified target (n = 140) followed by human adenoviruses (HAdVs; n = 25), human metapneumovirus (HMPV; n = 18), human bocavirus (HBoV; n = 15), human respiratory syncytial virus (HRSV; n = 12), human coronaviruses (HCoVs; n = 11), and human herpesvirus-6 (n = 11). HRVs were the sole agent detected in 37.8% (n = 31) of patients with suspected lower respiratory tract infection (LRTI). Genotyping of the HRV VP4/VP2 region resulted in a proposed subdivision of HRV type A into sublineages A1 and A2. Most of the genotyped HAdV strains were found to be type C. This study described the high microbial burden imposed by HRVs, HMPV, HRSV, HCoVs, and the newly identified virus, HBoV on a predominantly pediatric hospital population with suspected acute respiratory tract infections. Of 72 phlegm samples taken from children > 1 year-old in Chenzhou, a city in the central Chinese province of Hunan, 6 have tested positive since October 2005 to August 2006^ref. Human bocavirus has been found in nearly 5% of pneumonia patients in rural Thailand, mostly young children
• Dependovirus : first discovered in 1960s. Particles consist of 50% protein (VP1-3) and 50% DNA (5 Kb, packaging equal amounts of positive and negative strands)
• adeno-associated virus (AAV) 1
• adeno-associated virus (AAV) 2
• adeno-associated virus (AAV) 2H
• adeno-associated virus (AAV) 3
• adeno-associated virus (AAV) 3B
• adeno-associated virus (AAV) 4
• adeno-associated virus (AAV) 5
• adeno-associated virus (AAV) 6
• avian AAV
• canine AAV
• equine AAV
• ovine AAV
Over 40 genomic variants having been reported^ref. It appears that there are several major clades of related variants. Within these clades, many other individual variants appear to have been generated by recombination within the capsid coding sequence between different parental serotypes.
Genomics : 4680 nt

Proteomics :
• the 4 non-structural proteins designated as Rep78, Rep68, Rep52 and Rep40 are the only trans element in the AAV genome which are involved in the regulation of these events : they are necessary for the resolution of the termini during productive replication, accomplished by means of a site-specific, strand-specific nicking activity present in the longer Rep proteins, which are transcribed from the p5 promoter, and differ only at the C-terminus, where spliced and unspliced versions are both translated. These longer Rep proteins are also bifunctional transcriptional regulators, which generally activate AAV gene expression during productive infections and repress it during latency. The shorter Rep proteins are transcribed from the p19 promoter, which is embedded within the long Rep coding sequence. The shorter Reps are necessary for packaging single-stranded AAV genomes into capsids. They also modify the transcriptional regulatory activities of the longer Reps. Rep78/68 interacts with topoisomerase I binding, arginine/serine-rich (TOPORS) to enhance gene transcription. Rep68 interacts with the template-activating factor I/Set oncoprotein (TAF-I/Set) complex^ref. The N terminus of Rep binds the acidic domain of ANP32B, a member of the acidic nuclear protein 32 family which takes part in the formation of the template-activating factor I/Set oncoprotein (TAF-I/Set) complex; through this interaction, Rep was also able to recruit other members of the TAF-I/Set complex, including the ANP32A protein and the histone chaperone TAF-I/Set. Further experiments revealed that silencing of ANP32A and ANP32B inhibited AAV replication, while overexpression of all of the components of the TAF-I/Set complex increased de novo AAV DNA synthesis in permissive cells. Besides being the first indication that the TAF-I/Set complex participates in wild-type AAV replication, these findings have important implications for the generation of recombinant AAV vectors since overexpression of the TAF-I/Set components was found to markedly increase viral vector production^ref
• at the 3' end of AAV genome, the cap gene encodes 3 overlapping structural proteins VP1, VP2 and VP3. These 3 proteins are colinear and identical over their carboxy-terminal portion. VP2 and VP3 represent amino-terminal truncations of VP1. The typical AAV capsid consists of 60 molecules of capsid protein, with a ratio of 3:3:54 of VP1:VP2:VP3 in a nonenveloped icosahedral structure. The crystal structure has recently been published^ref. The structural determinants of AAV2 receptor binding to the heparan sulfate proteoglycan attachment receptor have also been delineated by various mutagenesis studies^ref1,ref2. The differences in binding affinity to different receptors among the various serotypes are likely to be accounted for by differences within these structural determinants, since the key heparin-binding residues are different on nonheparin-binding serotypes^{ref1, ref2}.
• inverted terminal repeats (ITRs) are 145-bp-long palindromic sequences which can assume a T shaped hairpin structure. This special configuration serves as the origin for viral DNA replication. In addition, the ITRs are essential for successful virus packaging, replication, integration and rescue of the vector genome. Recent studies also indicate that the ITR possess some transcriptional promoter activity, albeit relatively weak^ref. The Rep78 and Rep68 can both bind to the ITR at GAGY tandem repeats and nick duplex ITR in a site- and strand-specific manner. This cleavage reaction within the ITR allows the continuous replication of the AAV genome.
• D sequence is the only non-palindromic sequence in the ITR. Its 20-nucleotides contain :
• terminal resolution site (TRS)
• AAV packaging signal
A single ITR with 2 D sequences permits the replication and packaging of the AAV gernome. However, in the absence of the D sequence, the hairpin stuctures are insufficient for the encapsidation of the AAV genome. Although exact nucleotide sequences are not conserved among the identified AAV ITRs from various AAV serotypes, the overall T shaped hairpin structure is maintained. Generally, the Rep proteins from one AAV serotype can complement the ITRs from another AAV serotype. The only exception is AAV5, which has the least homology with any of the known AAV serotypes and its ITR has a unique TRS site.
Receptors :
• AAV1 uses ?
• AAV2 (the most commonly used serotype) uses^refheparan sulfate proteoglycan (HSPG)^ref (poorly expressed on the apical surface of polarized ciliated respiratory epithelial cells), and the FGFR-1 (ubiquitous) and a_vb₅ integrin as coreceptor^ref
• AAV3 uses heparan sulfate proteoglycan (HSPG)
• AAV4 uses O-linked sialic acid^ref
• AAV5 uses N-linked sialic acid^ref and PDGFRab (lung, central nervous system, muscle and eye)^ref
AAV vectors transduce cells by multiple pathways, including integration at nonhomologous chromosomal locations by an unknown mechanism.
• in absence of cell-stressing agents (helper functions), they integrate in a site specific manner (in the case of AAV2, ~ 70% of integration occurs in 19q13.3-qter, the adeno-associated virus integration site 1 (AAVS1)) through rep-mediated semihomologous recombination (only 30 bp homology) and establish long-term latency within mammalian cells. Existing spontaneous chromosome breaks facilitates vector integration, which has implications for their clinical use, as demonstrated in cells containing a specific chromosomal double-strand break created by the endonuclease I-SceI or multiple breaks created by treatment with etoposide or g-irradiation^ref
• in the other case they undergo lytic life cycle
=> asymptomatic infection is common in humans (at age 20, 85% has neutralizing Abs : 5-10% has vDNA in muscle cells !) and in many animal species
Used as transfection vector.
• Erythrovirus
• B19 virus / human parvovirus B19
  
Genomics : discovered in 1974; the 5.6-kb genome codes for only 3 major proteins, the 2 overlapping capsid proteins VP1 and VP2 and the non-structural protein NS1. Surprisingly high rate of evolutionary change, at approximately 10(-4) nucleotide substitutions per site per year. This rate is more typical of RNA viruses and suggests that high mutation rates are characteristic of the Parvoviridae^ref.
Receptor : erythrocyte P blood group antigen
Susceptibility : HLA-DRB1*01, DRB1*04 , and DRB1*07 alleles
Transmission : respiratory route.
Pathogenesis : B19 targets immature erythroid cells in the bone marrow. Autoantibodies produced in the wake of B19 infection include ANAs, anti-DNA, anti-SSA/SSB, and anti-phospholipids. Clinical resolution of acute infection is associated with the emergence of antiviral IgG, which is maintained lifelong^ref. However, although antibodies are of importance, evidence for an important role for cellular immune responses in the control of B19 infection is also emerging. In some individuals with apparently intact antibody responses, virus replication continues long term^ref. Readily detectable CD8⁺ T cell responses in three asymptomatic seropositive individuals have also been observed^ref. CD8⁺ T cells play an essential role in the control of viral infections by direct killing of virus-infected cells and through cytokine secretion. After a primary viral infection, naïve antigen-specific T cells expand clonally and undergo several differentiation stages, followed by a contraction phase mediated by apoptosis. Expression of the chemokine receptor CCR7 on memory T cells has been used to divide this population into central and effector memory subsets. CCR7⁺ “central” memory lymphocytes mostly home to secondary lymphoid organs and have a high proliferative capacity in response to antigen re-encounter. CCR7^- “effector” memory cells home to non-lymphoid organs and are capable of rapid effector function^ref. Peptide–MHC multimers can be used to further quantify and phenotype T cells bearing T cell receptors of appropriate peptide/HLA specificity^{ref1, ref2}. Amongst “effector” memory populations, a spectrum of phenotypes exists, as assessed by surface expression of markers such as CD27, CD28, and CD57, and intracellular expression of perforin. Amongst the viral infections studied, cytomegalovirus (CMV) is associated with the emergence of the largest long-term memory populations with the most “mature” phenotype, CD27/CD28 ^low, CD57 ^high, and often perforin positive^ref. The factors that ultimately determine the phenotype and function of these populations of lymphocytes are not fully understood, but continued exposure to antigen is thought to be important. Persistent infections such as HCV, EBV, and HIV also show antiviral populations that are “effector” (CD62L^low or CCR7^low), but show lower levels of maturation than CMV-specific responses^ref. B19-specific CD8⁺ T cell responses during and after acute adult infection was studied using HLA–peptide multimeric complexes. Surprisingly, these responses increased in magnitude over the first year post-infection despite resolution of clinical symptoms and control of viraemia, with T cell populations specific for individual epitopes comprising up to 4% of CD8⁺ T cells. B₁₉-specific T cells developed and maintained an activated CD38⁺ phenotype, with strong expression of perforin and CD57 and downregulation of CD28 and CD27. These cells possessed strong effector function and intact proliferative capacity. Individuals tested many years after infection exhibited lower frequencies of B₁₉-specific cytotoxic T lymphocytes, typically 0.05%–0.5% of CD8⁺ T cells, which were perforin, CD38, and CCR7 ^lowref
=> asymptomatic
=> papular-purpuric gloves-and-socks syndrome
=> erythema infectiosum / epidemic megaloerythema / "fifth" disease of the infant / "slapped cheek" syndrome after 5-15 days incubation :
• symmetric, bilateral, butterfly morbilliform maculopapular exanthema on face => arms and hips => trunk; followed by ...
• acute polyarthritis of hands, knees, whistles and ankles (5-10% of babies and 50-60% of adults, sometimes without feveror exanthema) self-limiting with 2-21 days. Acute B₁₉ infection can simulate early RA or SLE (butterfly rash over the cheeks, cytopenia, etc.)^{ref1, ref2}. In addition, there have been a few reports of erosive RA or SLE developing shortly after a B₁₉ infection, with positive PCR tests for B₁₉ DNA in synovial tissue or blood cells. Studies in large series indicate that B₁₉ is probably an extremely rare cause of RA or SLE. Vasculitides affecting the small vessels (Henoch-Schonlein purpura, Wegener's granulomatosis), medium-sized vessels (periarteritis nodosa), and large vessels (giant cell arteritis) can occur after B₁₉ infection
• in patients with hemolytic anemia or sickle cell disease it causes aplastic anemia for 7-10 days (it undergoes chronicization in immunocompromised individual); persistent infection in immunocompromised patients can lead to chronic bone marrow failure
• peripheral neuropathies
• meningitis
• encephalopathies
• myocarditis : myocardial endothelial cells, not cardiac myocytes, have been identified as parvovirus B19–specific target cells^ref. The high prevalence of parvovirus B19 genomes in 35% of patients with chronic dilated cardiomyopathy strongly suggests that chronic cardiac disease develops from previous parvovirus B19–associated myocarditis^ref.
• if a mother becomes affected in the second trimester of pregnancy => fetal hydrops, fetal death, and spontaneous abortion and acute hepatitis (liver is the fetal hematopoietic organ).
Laboratory examinations :
• giant basophilic proerythroblasts, erythroblasts with dog-eared cytoplasmic projections, vacuolated proerythroblasts, hemophagocytic syndrome like-cells, no Pelger anomaly
• identification of PVB19 by means of routine histology and immunohistology is only given in lytic infections occurring in transient aplastic anemia or nonimmune hydrops fetalis by the detection of viral inclusion bodies in erythroid precursor cells
• in all other PVB19-associated diseases, PCRmethods must be applied.
• in situ hybridization demonstrated that endothelial cells of the microcirculatory periphery of the heart and hepatobiliar system in lytic infections are PVB19-specific target cells in children and adults.
• specific IgG avidity index (AI)^ref
• unclassified Erythrovirus
• Human erythrovirus V9
• Human erythrovirus VX
• Parvovirus
• unclassified Parvovirus
• Human parvovirus 4
• unclassified Parvovirinae
• Human parvovirus 5
• dsRNA viruses : RNA templates and RNA-directed RNA polymerase (RdRP) are packaged together in a core or shell of viral proteins within which RNA synthesis occurs.
• Reoviridae : the reoviruses: a family of RNA viruses having a nonenveloped icosahedral virion 60–80 nm in diameter; virions have two protein shells, the particle with the outer shell removed being referred to as the core. The genome consists of 10 to 12 structural segments of linear double-stranded RNA (total MW 12–20 x 10⁶, 10–27 kbp depending on the genus). Virions contain 10–12 structural proteins, including a transcriptase, and are resistant to heat but sensitive to lipid solvents. Replication and assembly occur in the cytoplasm.
Transmission is by the fecal-oral route, by fomites, or by arthropod vectors.
Proteomics : fusion-associated small transmembrane (FAST) proteins of the fusogenic reoviruses are the only known examples of membrane fusion proteins encoded by nonenveloped viruses.
Some genera contain arthropod and plant pathogens. Vertebrate pathogens are included in the genera :
• Aquareovirus infect fresh- and salt-water fish and invertebrates; some species cause economically important diseases of fish.
• Coltivirus : tickborne vertebrate viruses having 12-segmented dsRNA genomes
Genomics : Coltivirus particles are 80 nm in diameter and have a core 50 nm in diameter. Electron microscopic studies^{ref1, ref2} have shown particles with a relatively smooth surface capsomeric structure and icosahedral symmetry. Most viral particles are nonenveloped, but a few acquire an envelope structure during passage through the endoplasmic reticulum^{ref1, ref2}. The buoyant density of CTFV in CsCl is 1.36–1.38 g/cm³. The virus is stable between pH 7.0 and 8.0 but loses infectivity at pH 3.0. CTFV can be stored at 4°C for 2–3 months in 50% fetal calf serum, 0.2 mmol/L Tris-HC1, pH 7.8, or for years at –80°C. Upon heating to 55°C, CTFV loses its infectivity. The virus is stable when treated with nonionic detergents (such as Tween 20) or with organic solvents (such as Freon 113 or its ozone-friendly substitute Vertrel XF), but viral infectivity is abolished by treatment with sodium deoxycholate or sodium dodecyl sulfate^ref (Attoui H, Mohd Jaafar F, de Lamballerie X, Mertens PPC. Coltivirus, Reoviridae. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: eighth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2005. p. 497–503). The genome consists of 12 dsRNA segments designated Seg-1 to Seg-12 in order of reduced molecular weight as observed during agarose and polyacrylamide gel electrophoresis. The genome contains 29,000 bp and segment size ranges from 675 bp to 4,350 bp^{ref1, ref2}. The genomic dsRNA of CTFV has an electropherotype similar to that of CTFV-Ca. CTFV produces a cytopathic effect (CPE) in mammalian cells, including human carcinoma cells, monkey kidney cells (buffalo green monkey [BGM] and Vero), hamster kidney cells (BHK-21), and mouse fibroblasts (L-929). Cells infected with CTFV develop granular matrices that contain viruslike particles in the cytoplasm. These structures are similar to viral inclusion bodies produced during orbivirus infections^ref. In addition, bundles of filaments (tubules) characterized by cross-striations and kinky threads are found in the cytoplasm and, in some cases, in the nucleus of infected cells^{ref1, ref2} (Attoui H, Mohd Jaafar F, de Lamballerie X, Mertens PPC. Coltivirus, Reoviridae. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: eighth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2005. p. 497–503). These tubules may also be comparable to those found in orbivirus-infected cells. > 90% of virus particles remain associated with debris after cell disruption. Sequence analysis of coltivirus genomes has shown that segment 6 of viral protein 6 (VP6) of CTFV is homologous to segment 7 (VP7) of EYAV. The amino acid sequence (residues 370–490) of VP7 of EYAV showed 50% similarity to the sarcolemmal-associated protein of the European rabbit O. cunniculus, which may be the major host of EYAV. By comparison, VP6 of CTFV showed no similarity with this rabbit protein^ref, which may be the result of insertion of a sequence encoding a lagomorph protein into segment 7 of EYAV. Reading through a stop codon, which is common in retroviruses and alphaviruses, was reported in coltiviruses, particularly in segment 9, where long and short proteins are produced from a single open reading frame^ref. Antigenic variation between CTFV strains is low, especially between strains from humans^ref. Distinct CTFV serotypes are difficult to define^ref, and immunity to reinfection has been observed^ref. CTFV from North America and EYAV from Europe show little cross-reactivity in neutralization assays. CTFV-Ca cross-reacted with CTFV, but not with EYAV, and may be a serotype of CTFV. Two species of coltiviruses have been identified: CTFV, with 2 serotypes represented by CTFV-F1 and CTFV-Ca, and EYAV. Overall identities between nucleotide sequences from segments 9, 10, 11, and 12 of CTFV strains range from 90% to 100%: 97–100% for segment 9, 96–99% for segment 10, 90–94% for segment 11, and 94–96% for segment 12. The degree of identity between nucleotide sequences of segments 1–12 of CTFV and EYAV isolates ranges from 55 to 88%^ref. The genome of CTFV contains 29,174 nucleotides, and that of EYAV contains 29,210 nucleotides^ref. All 12 segments of CTFV and EYAV have conserved sequences that are located at their termini. The motifs 5´-G/CACAUUUG-3´ and 5´-UGCAGUG/C-3´ are found in the 5´ and 3´ noncoding regions of CTFV, respectively, and the motifs 5´-GACAA/UUU-3´ and 5´-UGC/UAGUC-3´ are found in these noncoding regions in EYAV. The 5´ and 3´ terminal trinucleotides of all segments in both viruses are inverted complements^ref. Genome characterization has helped shed light on the origin of EYAV. Genetic findings support the hypothesis that EYAV was derived from a CTFV-like ancestor virus that was introduced into Europe through Asia when lagomorph ancestors migrated from North America 5–50 million years ago^ref. The antigenic and genetic relationships between CTFV and EYAV are further corroborated by their identical morphologic features, as analyzed by electron microscopy^ref.
• Colorado tick fever virus (CTFV) was isolated by Florio and others (Florio L, Stewart M, Mugrage ER. The etiology of Colorado tick fever. J Exp Med. 1946;83:1–10) in 1946 from human serum by injection into adult hamsters. The virus was adapted to egg and mice, and suckling mice became the routine isolation system for CTFV^{ref1, ref2} (Florio L, Stewart M, Mugrage ER. The etiology of Colorado tick fever. J Exp Med. 1946;83:1–10)

California hare coltivirus (CTFV-Ca), identified as strain S6-14-03, was isolated from the blood of the white hare, L. californicus, black-tailed jackrabbit), in northern California (outside the range of D. andersoni)^ref

Salmon River virus (SRV), which may be a serotype of both CTFV and CTFV-Ca, isolated from a person with moderately severe CTF-like illness in Idaho

Epidemiology : regions of the Rocky Mountains area and Pacific slope of the USA and Canada, where it causes CTF, a human disease initially confused with a mild form of Rocky Mountain spotted fever, which is caused by Rickettsia rickettsii. Antibodies to CTFV antigen have been detected in sera of humans in South Korea (C. Calisher, pers. comm.).
Transmission : a zooanthroponosis; vector : wood tick Dermacentor andersoni, but other ticks such as Dermacentor occidentalis, Dermacentor albopictus, Dermacentor arumapertus, Haemaphysalis leporispalustris, Otobius lagophilus, Ixodes sculptus, and Ixodes spinipalpisare also infected with the virus. CTFV is transmitted transstadially, but not transovarially. Infected larvae and nymphs can hibernate, and the nymphal and adult ticks become persistently infected. In certain rodents viremia can persist for >5 months. These ticks and rodents may provide hosts by which the virus could overwinter. The prevalence of viremia in rodents in a virus-endemic area ranges from 3.5% to 25%, and the prevalence in ticks ranges from 10% to 25%^ref. CTFV has a wide host range that includes ground squirrels, chipmunks, wild mice, wood rats, wild rabbits and hares, porcupines, marmots, deer, elk, sheep, and coyotes. Person-to-person transmission of CTFV can occur by blood transfusions (Philip RN, Casper EA, Cory J, Whitlock J. The potential for transmission of arboviruses by blood transfusion with particular reference to Colorado tick fever. In: Greenwalt J, Jamieson GA, editors. Transmissible disease and blood transfusions. New York: Grune and Stratton; 1975. p.175–96). This virus is included on the list of agents screened before bone marrow transplantation in the USA^ref. Prolonged viremia observed in humans and rodents is due to the intraerythrocytic location of virions, which protects them from immune clearance^{ref1, ref2, ref3}.
=> Colorado tick fever / mountain tick fever : 4-6 days incubation => high (biphasic) fever, leukopenia, arthromyalgia, nausea and vomiting, petechiae on limbs and maculopapular exanthema on trunk
Prevention : patients infected with CTFV show long-lasting immunity. An experimental vaccine was developed in the 1960s and produced long-lasting immunity, but production was stopped in the 1970s.

Eyach virus (EYAV) was isolated in Europe in 1976 from Ixodes ricinus ticks (EYAV-Gr) and in 1981 from Ixodes ricinus (EYAV-Fr578) and Ixodes ventalloi(EYAV-Fr577)^ref. Its antigenic relationship to CTFV was established by a complement-fixation assay^ref. Genome sequence analysis showed that CTFV and EYAV are closely related^refand confirmed the antigenic observations. Serologic surveys in France identified antibodies to EYAV in 1.35% of animals, including the European rabbit (Oryctolagus cunniculus), mice, mountain goats, domestic goats, sheep, and deer^ref. The presence of EYAV was suspected in Europe because anti-EYAV antibodies were detected in patients with neurologic disorders. However, the natural cycle of the virus is still unclear, and whether it circulates continuously in Europe is not known, although the rabbit O. cunniculus is suspected of being main host^{ref1, ref2}. In 2003, the virus was reisolated from I. ricinus ticks in Germany^ref
=> abrupt onset of fever, chills, headache, retroorbital pain, photophobia, myalgia, abdominal pain, and generalized malaise. Diphasic or triphasic febrile patterns have been observed, usually lasting for 5 to 10 days. Severe forms of the disease that involve infection of the central nervous system (CNS) or hemorrhagic fever, pericarditis, myocarditis, and orchitis have been rarely observed, mainly in children. Severity is sufficient to result in hospitalization of 20% of patients. Offspring of mice experimentally infected with CTFV showed teratogenic effects^ref. Mother-to-infant transmission has been reported in pregnant women. The incidence of complications in different reports of infection with CTFV has been reported as <7%^{ref1, ref2, ref3, ref4}. CTFV causes leukopenia (65% of infected humans), with mean leukocyte counts of 900/mL to 3,900/mL, and thrombocytopenia, with platelet counts of 20,000/mL to 95,000/mL^ref. Patients with neurologic disorders (meningitis, meningoencephalitis, encephalitis) show lymphocyte infiltration of cerebrospinal fluid (CSF), and the virus has been isolated from CSF. CTFV infections have been confused with other tickborne diseases such as Rocky Mountain spotted fever (a rickettsial disease), tularemia, relapsing fever, and Lyme disease. However, rash and leukocytosis distinguish Rocky Mountain spotted fever from CTF. Signs in the CNS confuse CTF with other causes of viral meningitis and encephalitis, including St. Louis encephalitis virus, Western equine encephalitis virus, and enteroviruses.CTFV can be isolated from blood because it is present in circulating erythrocytes for as long as 4 months^ref, and it infects the hematopoietic progenitor cells and remains sheltered in erythrocytes after maturation. Intracerebral injection of blood into suckling mice is considered the most sensitive isolation system. Reverse transcription–polymerase chain reaction (RT-PCR) was developed for diagnosis of CTFV infection, and this method detected human and tick virus isolates >3 days postinfection in experimentally infected mice^ref. As little as 1 genome could be detected by using a PCR assay^ref. Serologic diagnostic methods based on CTFV-infected cell cultures have also been developed^ref. These include 1) a complement-fixation test that is relatively insensitive because in 25% of patients complement-fixing antibodies are not detected and in 75% of patients these antibodies appear late after infection; 2) a seroneutralization assay for detection neutralizing antibodies that appear 14–21 days after onset of disease; 3) an immunofluorescence assay that uses CTFV-infected BHK-21 or Vero cells and is an easy and rapid test for detecting anti-CTFV antibodies; and 4) an enzyme-linked immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG that appear concurrently or a few days after neutralizing antibodies (peak 30–40 days after infection), However, IgM titers decrease sharply after day 45. An ELISA based on recombinant VP7 and a Western blot based on synthetic VP12 showed good sensitivity in detecting antibodies to CTFV^{ref1, ref2}. A complement fixation assay has been developed for detection of EYAV^ref. It detected anti-EYAV antibodies in 158 Czechoslovakian patients with encephalitis in whom tickborne encephalitis had been diagnosed. This population was also tested for tickborne encephalitis viruses (Kemerovo, Lipovnik, or Tribec) and antibodies to EYAV. Seventeen serum specimens (11%) had only anti-EYAV antibodies. The same test identified anti-EYAV antibodies in 8 (17%) of 47 patients with polyradiculoneuritis and meningopolyneuritis^ref. Recently, an ELISA based on recombinant VP6 of EYAV was developed. This test selectively identified anti-EYAV antibodies^ref. An RT-PCR assay based on the sequence of genome segment 12 has also been developed for specific detection of EYAV^ref
• Orbivirus, separable into at least 14 antigenically distinct groups, and infecting a variety of vertebrates, including humans. It includes the agents of bluetongue and African horse sickness. Mosquitoes, sandflies, and ticks are vectors.
• Kemerovo virus group
• Great Island complex
• Broadhaven virus
• Kemerovo virus : a tickborne virus that causes a benign febrile disease in western Siberia and Egypt
• Lipovnik virus
• Tribec virus
• Orungo virus group
• Orungo virus
=> febrile illness in Nigeria and Uganda
• Orthoreovirus infect a wide range of animals and are distributed worldwide. No causative relationship to any disease has been proved in humans, although reoviruses have been isolated from both healthy individuals and patients with a variety of diseases. In other mammals reoviruses are associated with respiratory and enteric disease, and in chickens and turkeys, with arthritis. Experimentally in mice, orthoreoviruses may cause a wide spectrum of disease, and viruses isolated from primates have been associated with neurological disease. Avian orthoreoviruses can cause severe disease outbreaks in domestic flocks but do not infect mammals
• Mammalian orthoreoviruses
• Mammalian orthoreovirus serotype 1
• Mammalian orthoreovirus serotype 2
• Mammalian orthoreovirus serotype 3
=> murine lymphoma^{ref1, ref2, ref3, ref4, ref5, ref6,ref7}, rabbit lymphoma^ref, human Hodgkin's lymphoma^ref and Burkitt's lymphoma^{ref1, ref2, ref3, ref4, ref5, ref6, ref7}
=> neonatal infection causes biliary ways atresia; murine chronic hepatitis^ref
Proteomics : reoviruses deal the host cell a double blow by activating apoptotic pathways and inhibiting DNA damage repair genes. Both mechanisms ultimately lead to cell death.
• viral attachment protein sigma1 (an elongated fiber comprised of an N-terminal tail that inserts into the virion and a C-terminal head that extends from the virion surface) binds to F11 receptor (F11R) / junction adhesion molecule A (JAM-A)^ref and induces apoptosis (mitochondrial release of Smac/DIABLO, down-regulation of survivin, XIAP, and IAP1)^ref. JAM-1 was the first of a family of related proteins (JAM family) to be discovered. Two proteins with structural and sequence similarities to JAM-1, named JAM-2 and JAM-3, have been identified more recently. JAM-1 is specifically localized at the tight junctions of epithelial and endothelial cells and is involved in the regulation of junctional integrity and permeability. This function is attributed to its ability to interact in a homophilic manner. JAM-1 can also bind in a heterophilic manner as it serves as a ligand for integrin LFA-1 (CD11a/CD18), and plays a key role in the process of leukocyte transmigration. In addition, JAM-1 is also a receptor for reovirus, and is a platelet receptor involved in platelet adhesion and antibody-induced platelet aggregation^ref.
Transmission : enteric or respiratory route.
=> subclinical infections
=> mild gastroenteritis in newborns and babies
=> URT infection in newborns and babies
=> mild URT infection (acuterhinitis or pharyngotonsillitis)
• Rotavirus have a wheellike appearance : 11 structural segments of linear double-stranded RNA
• Group B rotaviruses
• Human rotavirus B
• Group C rotaviruses
• Human rotavirus C
• Human rotavirus
• Human rotavirus (serotype P13 / strain 1845)
• Human rotavirus 1
• Human rotavirus 2
• Human rotavirus 3
• Human rotavirus 4
• Human rotavirus 9
• Human rotavirus A (VP6 Ag)
• Human rotavirus G (pararotaviruses or atypical rotaviruses)
• Human rotavirus (serotype G / strain B37)
• Human rotavirus (serotype G / strain RK9)
• human rotavirus DG8
• Human rotavirus serotype G1
• Human rotavirus serotype G2
• Human rotavirus serotype G3
• Human rotavirus serotype G4
• Human rotavirus serotype G6
• Human rotavirus serotype G8
Epidemiology : first reported in 1973; worldwide every year 111 million children under age 5 become mildly ill, 25 million sick enough to require a clinic visit, 2 million require hospitalization, and 440,000-600,000 die (82%  in the poorest countries)^ref; it is the most common cause of severe diarrhea in children in the USA. Virtually all children have one or more rotavirus infections in the first 5 years of life. Each year in the USA, rotavirus is responsible for approximately 500,000 physician visits, 70,000 to 120,000 hospitalizations and 200 infant deaths. It is a seasonal disease in the USA with the vast majority of the disease occurring in the winter and spring months. Outbreaks affecting the elderly in institutionalized settings are not uncommon.
• since 29 Jan to 24 Feb 2004, 28 255 people (of whom 17 032 are under 5 years of age; 15-60% laboratory confirmed) and 50 children have died in Guatemala. During the first 3 weeks of the outbreak, the increase in relation to 2003 was 9%, falling to 4% in the 4th week. The outbreak has affected above all the health districts of Ixcan, Peten Sur Oriente, and Escuintla, but has also spread to Guatemala, Sacatepequez, Suchitepequez, Quetzaltenango, San Marcos, El Progreso, and Zacapa.
• since Jan 2004, 1350 cases and 2 deaths in the resort town of Montego Bay, Jamaica. During 2003, > 28 000 cases (14 deaths) of gastroenteritis were reported in this Caribbean country of 2.6 million residents, up from about 20 000 (5 deaths) in 2002
• since February 2004, 108 confirmed cases have been reported of rotavirus-associated diarrhea in El Salvador, of which 86 percent have occurred in children under 2 years of age. The Departments most affected have been Santa Ana (with 58.3% of the cases) and San Salvador (with 20.4%). To date, no deaths have been reported.
Proteomics :
• NSP3 / NS34 is functional homolog of the cellular poly(A) binding protein (PABP) that interacts with ubiquitous tetratricopeptide containing protein RoXaN and binds to viral mRNA 3' consensus sequences and circularizes mRNA via interactions with eIF4G1
• NSP4 enterotoxin. Diarrhoea may be caused by several mechanisms including :
• malabsorption that occurs secondary to the destruction of enterocytes of the duodenum and upper ileum
• villus ischaemia and activation of the enteric nervous system (ENS) that may be evoked by release of a vasoactive agent from infected epithelial cells in the absence of significant pathologic lesions or enterocyte damage and may be cyclic nucleotide dependent
• intestinal secretion stimulated by the intracellular or extracellular action of NSP4 => [Ca²⁺]_i elevation => age-dependent halide ion movement across the plasma membrane, transepithelial Cl^-secretion, and, unlike many microbial enterotoxins, initial cyclic nucleotide independence to secretory diarrhea. NSP4-mediated [Ca²⁺]_i mobilization may further facilitate diarrhea by signaling through other Ca²⁺-sensitive cellular processes (cation channels, ion and solute transporters) to potentiate fluid secretion while curtailing fluid absorption
Both phases of diarrhea occur in the absence of significant inflammation
• trypsin cleavage of VP4 primes the virus for entry by triggering a rearrangement that rigidifies the VP4 spikes into  a coiled-coil stabilized trimer. VP4 also undergoes a second rearrangement, in which the oligomer reorganizes and each subunit folds back on itself, translocating a potential membrane-interaction peptide from one end of the spike to the other. This rearrangement resembles the conformational transitions of membrane fusion proteins of enveloped viruses^ref.
• viroplasms are discrete structures formed in the cytoplasm of rotavirus-infected cells and constitute the replication machinery of the virus. The non-structural proteins NSP2 and NSP5 localize in viroplasms together with other viral proteins, including the polymerase VP1, VP3 and the main inner-core protein, VP2. NSP2 and NSP5 interact with each other, activating NSP5 hyperphosphorylation and the formation of viroplasm-like structures (VLSs)^ref. Phosphorylation of Ser⁶⁷ within the SDSAS motif (amino acids 63-67) by casein kinase 1a is required to trigger hyperphosphorylation of NSP5 (4 serines (Ser¹⁵³, Ser¹⁵⁵, Ser¹⁶³, and Ser¹⁶⁵) within an acidic region with homology to casein kinase II (CKII) phosphorylation sites^ref) by promoting its activator function^ref. Expression of anti-NSP5 intrabodies in rotavirus-infected cells largely reduces the assembly of viroplasms and CPE. Replication of dsRNA is partially inhibited, despite there being no reduction in virus titre, demonstrating for the first time a key role for NSP5 during the virus replicative cycle^ref. Genome segment 11 encodes the non-structural protein NSP5 and, in some strains, also NSP6. NSP5 is produced soon after viral infection and localizes in cytoplasmic viroplasms, where virus replication takes place. RNA interference by small interfering (si) RNAs targeted to genome segment 11 mRNA of 2 different strains blocked production of NSP5 in a strain-specific manner, with a strong effect on the overall replicative cycle : inhibition of viroplasm formation, decreased production of other structural and non-structural proteins, synthesis of viral genomic dsRNA and production of infectious particles^ref. Fusion of tags induces spurious phosphorylation of rotavirus NSP5^ref. A strong interaction of VP1 with NSP5 but only a weak one with NSP2 was found in co-transfected cells in the absence of other viral proteins or viral RNA. By contrast, VP2 could not be co-immunoprecipitated with anti-NSP5 antibodies or NSP5 with anti-VP2 antibodies. A tagged form of VP1 co-localizes in viroplasms and in VLS formed by NSP5 and NSP2. The tagged VP1 was able to replace VP1 structurally by being incorporated into progeny viral particles. When applying anti-tag-VP1 or anti-NSP5 antibodies, co-immunoprecipitation of tagged VP1 with NSP5 was found. Using deletion mutants of NSP5 or different fragments of NSP5 fused to EGFP, the 48 C-terminal amino acids were identified as the region essential for interaction with VP1^ref
• VP7 outer capsid protein of rotavirus induces polyclonal B-cell activation^ref and has homology to transglutaminase 2 / tissue transglutaminase (tTG), C polypeptide, so molecular mimicry could cause celiac disease^ref
The 2 glycoproteins, one structural (VP7) and one non-structural (NSP4), mature and remain in the ER thanks to 3 amino acids in the N terminus and a region between amino acids 85 and 123 in the cytoplasmic region of NSP4, respectively^ref
Transmission : fecal contamination of food and water (stable in the environment and can remain viable for long periods of time. This permits transmission from contact with contaminated surfaces, water, or food)
=> acute gastroenteritis after 1-4 days incubation : nausea and vomiting, diarrhea, abdominal pain, and fever. Dehydration (sunken eyes) is common and if not dealt with promptly has serious consequences. Severe diarrhea and dehydration occur primarily among children 3 months to 35 months of age. In 2 patients with rotavirus gastroenteritis who developed encephalopathy, rotavirus RNA was detected in the cerebrospinal fluid (CSF) by RT-PCR; in 1 patient, rotavirus RNA was detected on 2 occasions 3 weeks apart. There are increasing reports of cases in which patients who have seizures after an episode of rotavirus diarrhea have evidence of rotavirus in their CSF. A search of 2 large hospital discharge databases suggested that seizures are noted as part of the discharge diagnosis in the records of, at most, <4% of patients with rotavirus diarrhea versus 7% of patients with bacterial diarrhea. Although evidence suggesting that rotavirus is a cause of central nervous system sequelae remains inconclusive, the 2 case reports presented in this study further illustrate a possible association. Further study is required to determine whether detection of rotavirus in CSF represents a true pathogen, CSF contamination that occurs at the time of lumbar puncture or in the laboratory, or carriage of rotavirus RNA in trafficking lymphocytes^ref : a case of rotavirus cerebellitis was reported^ref
Laboratory examinations : > 3 watery or looser-than-normal stools within a 24-hour period or forceful vomiting, along with the detection of rotavirus by enzyme immunoassay in a stool specimen obtained within 14 days after the onset of symptoms. G serotypes were identified by one-step RT-PCR analysis followed by sequencing^ref. All rotavirus-positive stools were to be evaluated for vaccine strains by viral culture with the use of a plaque assay and RNA electropherotyping. Electron microscopy shows abundance of virus particles in the feces; ethyl dodecanoate (which smells of pears) in diarrhea
Therapy : approximately 1 out of every 40 children with gastroenteritis caused by rotavirus will require hospitalization and therapy providing fluids intravenously. Compliance with the oral-rehydration standards set by the global WHO strategy for Integrated Management of Childhood Illness (IMCI) is extremely important in these cases.
Prevention : there are no approved attenuated vaccines for rotavirus. Efforts to develop an effective and safe vaccine resulted in licensing in 1998 of a live oral vaccine (RotaShield) that was withdrawn less than one year later, after 9 reports of intussusception occurred within the 1st 7 months of vaccine use, more than double the cases reported in the previous 7 years. Intussusception occurs when the intestine telescopes into itself, causing an obstruction of the bowel that may have to be repaired surgically. An investigation of vaccinated infants confirmed that the vaccine was indeed the cause of the complication. Most of these infants had intussusception shortly after their vaccination. The risk of intussusception was 10 times higher than normal, and within the 1st 7 days after vaccination, the risk was 14 times higher than normal. This experience with RotaShield has resulted in the development of new candidate rotavirus vaccines that are currently in late phase III clinical trials. One of these vaccines, GlaxoSmithKline's Rotarix, was licensed in July 2004 to be used in Mexico^ref.
Web resources : International Rotavirus Symposium
• Seadornavirus (Southeast Asian dodeca RNA virus^ref : Attoui H, Mohd Jaafar F, de Lamballerie X, Mertens PPC. Seadornavirus, Reoviridae. In: Fauquet CM, Mayo MA, Maniloff J, Desselberger U, Ball LA, editors. Virus taxonomy: eighth report of the international committee on taxonomy of viruses. London: Elsevier/Academic Press; 2005. p. 504–10):
Epidemiology : these viruses are endemic in Southeast Asia, particularly Indonesia and China. BAV was first isolated in 1987 from CSF (2 isolates) and sera (25 isolates) of patients with encephalitis in southern China (Yunnan Province). Numerous isolates were also obtained from other patients with encephalitis^{ref1, ref2} (33,34). A virus described as an isolate of BAV was identified in western China (Xinjiang Province) from patients with fever and flulike manifestations (Li QP. First isolation of 8 strains of new orbivirus (Banna) from patients with innominate fever in Xinjiang. Endemic Dis Bull. 1992;7:77–82). Virus isolates from pigs and cattle with genomes having the same electropherotype as BAV were also reported^ref. The isolation from mosquitoes of 12 segmented dsRNA viruses antigenically related to BAV has been reported in various provinces of China, including Beijing, Gansu, Hainan, Henan, and Shanshi, and in central Java, Indonesia. BAV is now classified as a biosafety level 3 arboviral agent^ref.
Genomics : Seadornavirus has 7 structural proteins, 5 of which are present in the core^ref. The viruses are icosahedral with a diameter of 60–70 nm, and the core has a diameter of 50 nm. The surface of virus has spikes that are similar to those of rotaviruses. The viruses are stable at pH 7.0, and acidity decreases their infectivity (which is lost at pH 3.0). Purified virus can be stored at 4°C or for long periods at –80°C. Viral infectivity is decreased considerably upon heating to 55°C. Organic solvents such as Freon 113 or Vertrel XF can be used for purification of viral particles from cell lysates and do not affect infectivity. The seadornavirus genome consists of 12 segments of dsRNA known as Seg-1 to Seg-12 in order of decreasing molecular mass observed by gel electrophoresis. The genome of BAV or KDV is 21,000 bp, and the segment length ranges between 862 bp and 3,747 bp. During replication, viruses are found in the cell cytoplasm within vacuolelike structures that are believed to be involved in morphogenesis^ref. Seadornavirus isolates replicate in various mosquitoes cell lines such as C6/36 and AA23 (both from Ae. albopictus), A20 (Ae. aegypti), and Aw-albus (Ae. W. albus). > 40% of the virus particles are released into the culture medium before cell death and massive CPE (fusiform cells). Infected cells are not lysed, and the virus leaves cells by budding, thus acquiring a temporary envelope^ref. Late infection results in cell lysis from cell death. Intracellular radiolabeling of viral polypeptides has shown termination of host cell protein synthesis^ref. In addition to its capacity to replicate in a large number of mosquito cell lines, LNV is the only seadornavirus that replicates in a variety of transformed or primary mammalian cell lines such as Hep-2 (human carcinoma cells), BGM, Vero, BHK-21, L-929, and MRC-5 (human lung fibroblasts). Infection with LNV results in a massive lytic effect and also kills adult mice. Antigenic relationships between seadornaviruses were investigated by using mouse immune sera. BAV from southern China and Indonesia and KDV fr