Papovaviridae Subfamily polyomavirinae: 12 members Subfamily papillomavirinaae: PA: papilloma viruses PO: polyoma viruses VA: simian vacuolating

ing viruses (SV-40) 45 nm, circular covalently closed dsDNA Replicates in nucleus Narrow host range

Polyomaviruses that infect humans SV-40: contaminated poliovirus cultures JCV: PML progressive multifocal leukoencephalopathy BKV: ~80$ population infected JCV and BKV are highly related

Virion structure and genomic organization

Early proteins

SV-40 replication

Interactions of T Ag

Only in nucleus, receptor mediated endocytosis, cell lysed by replication of virus

Binds pRb and released E2F transcription factors induce cyclin A/E cell cycle progression Binds p53 so it cannot keep cell cycle in check

3 structural proteins: VP1, VP2, VP3 Large T Ag: DNA binding protein Complexed w/ histones (H2A, H2B, H3, H4) Site II: autoreg of early mRNA Early and late regions: Site I: initiates DNA synthesis Early: transcribed after genome enters Has helicase activity, interact nucleus, large and small T/t Ag w/ tumor suppressor genes Late: late in infection after DNA replication (Rb, p53), induces genomic starts, VP1-3, agnoprotein instability VP1: interact w/ host cell receptor Small t Ag: VP2: interact w/ cellular membrane Dispensible for lytic cycle, a/w Transcription is bidirectional (early and late mRNA from opposite protein phosphatase 2A strands of DNA) Polymovirus diseases in humans JC virus: BKV: Enters through respiratory tract Persists in kidney, shed in urine Virus in B lymphocytes Most adults seropositive Persists in brain and seeded during course of Tenal disease in immunocompromised (PVAN) primary inf; persists indefinitely in kidney Isolated from tumors (adenomas of pancreas, Causes PML (rare demyelinating disease of CNS) brain tumors) Most in immunocompromised patients SV-40 Symptoms: impaired speech/vision, mental Causes tumors in rodents deterioration, paralysis, blindness, Found in human tumors like osteosarcoma, sensory abnormalities mesotheliomas, meningiomas Death w/in 3-6 mo after onset (longer Polymavirus Associated Nueropathy (PVAN) after HAART) 1-10% renal transplant patients Target in CNS: oligodendrocyte, Reactivation of BKV causing enlarged cells w/ nuclei full of Epithelial cells of tubules/collecting ducts mostly viral particles affected renal dysfunction/failure

Papillomavirus 55 nm, icosahedral, nonenveloped, dsDNA Replication in nucleus Resistant to culturing Human papillomaviruses: more than 100 types 60 cutaneous 40 mucosal: 16, 18 are high risk; 6, 11 are low risk

Virion structure and genome Genome encodes 8 proteins: Early or late Long central region w/o ORFs Early ORFs sufficient for transformation L ORFs in productively infected cells Capsid contains 2 structural proteins: L1: ~80% total viral protein L2: minor protein DNA a/w cellular histones chromatin like complex Red/green = early, red = oncogenic, orange = late Condyloma acuminate Anogenital warts 90% from HPV-6/11 Rarely become malignant

Characteristics High degree of species specificity Infections only surface squamous epithelia Most common clinical manifestion = warts

Replication cycle Initially infects proliferating basal cells Does not replicate in basal cells st After 1 amplification; virus maintained in proliferating basal cells nd 2 amplification in differentiating cells Differentiation into keratinocytes triggers virus into lytic cycle

Immune evasion opportunity for immune system to detect HPV proteins b/c virus not in APC and doesnt lyse cells Low levels of E6/7 in basal epithelium L1/2 capsid prot in terminally differentiated squamous cells, which evade immune cells Infected keratinocytes less susceptible to CTL lysis Papillomavirus Early Proteins Integration of HPV genome into host cell chromosome usually results in inactivation of E2 (disrupted E2 ORF) E1/E2 involved in genome replication and transcriptional control E1: ATPase activity, helicase activity, DNA binding activity, interacts w/ DNA polymerase a-primase complex E2: transcriptional activator or repressor, represses E6/7 Mutations in E2: disrupt transformation, replication, regulation Early region controlled by E2 Not needed for DNA replication, but makes it more efficient E4: promot productive phase of papillomavirus life cycle E5: enhances activity of epidermal growth factor during productive stage; binds EGF receptor cell division E6 oncoprotein: binds p53, causes # cell divisions E7: a/w cyclin A/E and p21/27 (cyclin-dependent inhibitors), also a/w histon deacetylases to maintain episomal state of genome Poxvirus Most complex and largest viruses Linear dsDNA Only DNA viruses that replicate exclusively in cytoplasm Encodes all proteins for mRNA/DNA synthesis Vaccination/Erradication Edward Jenner w/ cowpox Why was it eliminated? humans are only host, single serotype, easily recognized disease (quarantine), vaccine was stable and inexpensive, scar = successful immunization

Common/Plantar Common: Verruca vulgaris; HPV2/4 Plantar: pressure point of foot, HPV-1/2/4

Cerivcal cancer HPV 16/18 99.7% of all cervical cancers harbor some HPV Second most common cancer in world; most common Ca in women of developing countries CIN1 can be cleared; CIN 2/3 cancer in decades

HPV Vaccine L1 protein for HPV 6, 11, 16, 18 Produced by recombinant DNA technology L1 proteins self-assemble into virus like particles (VLP, noninfectious, but highly immunogenic) Vaccine schedule: Approved for females 9 to 26 3 doses a 0, 2, and 6 months

Smallpox Inhalation or transmission by scabs Multiply in URT lymphatic macrophages LN primary and secondary viremia (hemorrhages of small BV, spleen, liver, BM, all organs) Two strains: variola major (mortality) and minor rd Abrupt fever/prostration, macular rash on 3 day vesicles that became pustular, ulcerated, scabbed and head w/ scarring Cell mediated immunity for all poxvirus infections

Orf virus Poxvirus of sheep and goats transmitted by direct contact w/ animal Single lesion that becomes granulomatous Regress w/in 25-35 days

Molluscum contagiosum Nodular to wart-like lesions Trunk, genitalia, proximal extremities Groups of 5-20 lesions Incubation: 2-8 weaks

Molluscum bodies

Parvoviruses/Family Parvoviridae Smallest virus, about size of ribosome ssDNA ss genome has inverted repeats to form hairpin loops + and strands packaged separately Family Parvoviridae Subfamily Parovirinae: infects vertebrates Genus parvovirus: warm blooded Genus erythrovirus: B19 Genus dependeovirus: AAV (adenoassociated virus), requires co-infection w/ adenovirus or herpes virus; vectors for gene therapy B19 virus Transient Aplastic Crisis: Patients w/ underlying hemolysis get TAC = abrupt cessation of RBC production Pnt must be acutely ill Symptoms: fatigue, lassitude, confusion, congenital heart failure Treat w/ blood transfusion Adenoviruses Non-enveloped icosahedral virus w/ fibers at vertices Linear dsDNA 42 serotypes, 1-7 most common Replication in nucleus Can cause inclusion bodies: virus particles in cytoplasm and nucleus Causes variety of human diseases and clinical syndromes (respiratory, GI, eye, pneumonia, cystitis, hepatitis, etc)

Genome and transcripts (autonomous)

Replication In nucleus, cells must be in S-phase Host DNA polymerase involved Ss displacement model (no lagging strand) Terminal sequence = primers; doesnt need other cellular proteins like topoisomerases Predicts site specific cleavage of replicative intermediates (NS1 protein)

Two ORFs that dont overlap Left: non-structural NS1, NS2 (red) Right: viral coat proteins Pure red cell aplasia Pnt w/ underlying immunodeficiency BM suppression, anemia Hydrops fetalis Seronegative pregnant woman infected w/ B19 virus Virus crosses placenta, infects fetus, kills erythrocyte precursors, causing anemia, congestive heart failure, and spontaneous abortion Diagnosis Detection of Ag: rapid diagnosis, from nasopharyngeal aspirates and throat washings Virus isolation: from nasopharyngeal aspirates, throat swabs, and fecus Serology: retrospective diagnosis, CFT widely used Adeno-associated virus (AAV) Require coinfection w/ unrelated helper virus (adenovirus, herpesvirus) Establish latent infections by integrating into chromosome 19 (homologous recombination) Not a/w tumor formation 5 serotypes of human AAV Studied as potential vector for gene therapy Treatment/prevention No specific antiviral therapy Vaccine against adult RDS: live adenovirus (4, 7, 21) in coated capsids, give to new recruits for armed forces

Mechanism of spread within body

Incubation ~9 days