Human Papillomavirus And Polyomavirus

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej

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Note on Papillomaviruses and Polyomaviruses These two genera, which were once grouped together with vacuolating viruses in the same family of Papovavidae, are now classified separately. Human health impact ● associated with cervical cancer (at least 85% of cervical carcinomas contain integrated HPV-DNA.) ● cause different kinds of warts such as condylomata acuminata found on the vulva and cervix and in the vagina in women, and on penis shaft, perianal skin, and anal canal in men. ● cause asymptomatic disease in healthy persons, but is reactivated to cause renal disease or PML, progressive multifocal leukoencephalopathy, in immunosuppressed ● may oncogenically transform a nonpermissive cell. Human papillomaviruses (HPV) >100 types (genotypes, not serotypes, to distinguish by cross-hybridization) 16 groups (A to P) Two types: Cutaneous & Mucosal HPV (seen in phylogenetic trees of E6 gene) Virion features 1. 2. 3. 4. 5. 6.

icosahedral capsid 52-55 nm, without envelope two structural proteins 72 capsomeres circular d/b stranded DNA 8 kb 7-8 early genes (E1-E8) 2 late genes (L1-L2): (expressed only in terminally differentiated upper layers) 7. All genes on plus strand HPV pathogenesis 1. Species-specific DNA viruses 2. Types are very tissue-specific 3. Different diseases (warts, genital/ oral/ conjunctival papillomas)

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej

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4. Lytic infections in permissive cells, but cause abortive, persistent, latent, or immortalize in nonpermissive cells 5. Virus accesses the basal cell layer through breaks in the skin 6. usually takes 3-4 months to develop warts. 7. Viral infection remains local and generally regress spontaneously but can recur. 8. HPV infection is hidden from immune responses and persists 9. Certain types are associated with dysplasia that may become cancerous with the action of cofactors. (40-70% of the mild dysplasias spontaneously regress) 10. DNA of specific HPV types is present (integrated) in the tumor cell chromosome 11. HPV-1, 2, 3, and 4 infect hands and feet, 12. HPV-6, 11, 16, 18, 31, 33, and 45 most commonly infect mucosal epithelium in anorectal tract & orolaryngeal cavity. (more than 30 types) 13. HPV-2 & 57 infect skin & genital mucosa. 14. HPV-16 associated with cervical cancer 15. In the following figure, genes E1&E2 are frequently disrupted by integration and gene E5 is often lost or not expressed after integration[1].

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej

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16.The virus-induced increase in cell number causes the basal and the prickle cell layer (stratum spinosum) to thicken. 17. As the basal cell differentiates, the specific nuclear factors expressed in the different layers and types of skin and mucosa promote transcription of different viral genes. 18. In a laryngeal papillomas, malignant conversion has been described, usually after radiotherapy to treat the initial lesion. Immunity Humoral and cell-mediated immunity developed. Regression is usually the result of cellular immunity. Cell-mediated immunodeficiency (1° or 2°) increases a risk of developing warts which can be extensive, persistent or recurrent and likely to progress. In a case of selective depletion of specific T cell clones (rare genetic skin disorder epidermodysplasia verruciformis, EV), for example, large plane warts from virus types such as HPV5 and 8 develop and persist for life. Genes (HPV-16) E1 - binds at Ori >> promote viral DNA replication and has helicase activity. - episomal maintenance [1] E2 - binds DNA >> helps E1, activates viral mRNA synthesis (binds to an enhancer site on the LCR can upregulate transcription of E6 & E7.) Lack E3 E4 - virion maturation [1], disrupts cytokeratins to promote release E5 - (oncoprotein) activates EGF receptor to promote growth (Not all Pvs possess and E5 gene.) E6 - binds p53 and promotes its degradation ● p53 functions to induce cellular arrest to allow repair of DNA damage E7 - binds and inactivates p105RB ● responsible for immortalizing properties of HPV-16&18 ● Rb is required for terminal differentiation of keratinocytes. Binding to it prevents differentiation and allows continued cell growth and viral expression. L1 - major capsid proteins (group- and type-specific determinants) L2 - minor capsid proteins (type-specific determinants) URR = upstream regulatory region (sometimes called LCR; long control region)

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej

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Epidemiology 1. Transmission: direct contact, sexual contact (STD), during birth (oropharyngeal lesions) 2. Painting with 5% acetic acid is used to detect subclinical infection. 3. Viruses found worldwide 4. No seasonal incidence 5. HPV-16, 18, 31, 45, 33&35[1] high risk (10% of infected develop cervical dysplasia), Types 16 & 18 are associated with malignant and premalignant lesions of the cervix and anogenital tract. (HPV-6, 11 low risk, common in benign vulval or penile warts, called condylomata acuminata) 6. most common types associated with invasive cancer HPV-16 (in Europe) and 18 (in Indonesia) 7. 2nd leading cause of cancer death in women in USA 8. Risk factors: multiple partners, smoking, family history, immunosuppression, human cofactors include genetic background, seminal fluid factors and immune status 9. Avoiding contact is the best way to prevent Lab diagnosis 1. Histology Hyperplasia of prickle cells (acanthosis), Excess production of keratin (hyperkeratosis) Hypertrophy of the basal layers and disorganization of the epidermal structure. 2. Pap smear Perinuclear cytoplasmic vacuolization, called koilocytosis (vacuolated cytoplasm), which can be seen in the case records by Goldstein, MA et al 2009 (freely accessible on-line) [4]. Kilocytes, however, are not always present, are not sufficiently specific for HPV and cannot differentiate between low and high risk HPV types[1]. Squamous epithelial cells are rounded and occur in clumps indicating HPV- infected cells. 3. DNA probe, PCR >> used to establish Dx & typing 4. not grow in cell culture (difficult) 5. Detection of HPV antibodies is rarely used (the detection shows evidence

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej

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of past exposure rather than current infection and are suitable for epidemiology studies.)

Human Polyomaviruses poly (many) and oma(tumour) no documented association with any naturally occuring tumour of man. Human polyomaviruses are BK and JC viruses Features 1. icosahedral capsid 42-45 nm (smaller), without envelope 2. 72 capsomeres 3. circular d/b stranded DNA 5 kb 4. genome divided into early, late, and non-coding regions 5. T proteins (large & small T antigens) on one strand 6. Early regions ● Large T : Regulation of early & late messenger RNA transcription; DNA replication; Cell growth promotion, immortalization, and transformation (binds to p53 & p105RB). ● Small T : viral DNA replication 7. Late regions (capsid proteins, VP1 (major& VAP), VP2, VP3) on the other strand >> host range & infectivity 8. non-coding region on both strands 9. genome replicate bidirectionally 10.virus is released by cell lysis Pathogenesis ● ●

JC virus : species- and tissue-specific Reactivations of BK and JC viruses are quite common in pregnancy, with viruria being detected in 3-7% of women, especially during the second and third trimesters. (persistent viruria, more illness, premature & jaundiced babies)

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej

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Epidemiology ● ●

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Ubiquitous Seropositive prevalence is similar in other countries ● BK virus: 30% (age < 3), 90% (age >5) have antibody to the virus. ● JC virus: 5% (pre-school), 30% (<17), 60% (adult) 10% of AIDs patients >> PML (fatal approx. 90% of all cases)

Lab diagnosis ● ●

PML: PCR in CSF In situ immunofluorescence, immunoperoxidase, DNA probe analysis, and PCR

Note on Human Papillomaviruses and Polyomaviruses (1/2552) S. Saengamnatdej ● ●

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Analysis of CSF, urine, or biopsy material Urine cytologic tests can reveal the presence of the viruses by revealing the existence of enlarged cells with dense, basophilic intranuclear inclusions resembling those induced by CMV. Detect antibody to BK virus & JC virus : hemagglutination inhibition and ELISA (negative results almost always exclude a diagnosis of PML)

References 1. Cubie, H. Papovaviruses; Warts: warts and cancer; progressive multifocal leucoencephalopathy. In Greenwood, D, Slack, RCB, Peutherer, JF (eds.) Medical Microbiology: A guide to microbial infections: pathogenesis, immunity, laboratory diagnosis and control. 16th ed., 2006, Churchill Livingstone, p.429-437. 2. White DO, Fenner FJ: Chapter 18 Papovaviridae. Medical Virology, 4th ed., San Diego, 1994, Academic Press. p. 294-305. 3. Murray, PR, Rosenthal, KS, Pfaller, MA. (eds.) Chapter 52 Papillomaviruses and Polyomaviruses. Medical Microbiology, 5th ed., Philadelphia, 2005, Elsevier Mosby. p.523-531. 4. Goldstein, MA, Goodman, A., del Carmen, MG, and Wilbur, DC. Case 10-2009: A 23Year-Old Woman with an Abnormal Papanicolaou Smear. The New England Journal of Medicine. March 26, 2009, p.1337-1344.