6/01: Papillomaviruses, polyomaviruses, and adenoviruses (Small DNA viruses) 6/10: Herpesviruses

1. 6/01: Papillomaviruses, polyomaviruses, and adenoviruses (Small DNA viruses) 6/10: Herpesviruses (Large DNA viruses) 6/15: Retroviruses (RNA in virions, integrated viral DNA in chromosomes)

2. 40~50 nm 70~90 nm 100~200 nm

3. >100 kb 5~40 kb

4. HPV EBV, KSHV HTLV HBV HCV • Viruses with oncogenic potential: • Papillomaviruses • Polyomaviruses • Adenoviruses • Herpesviruses • Retroviruses • Hepadnaviruses • Flaviviruses

5. Viral genome replication in nucleus!

6. I. Viral particle • Viral genome • Life cycle • Infection and immunity • Diseases • Diagnosis • Treatment and control

7. Papillomaviruses

8. Viral particle: nonenveloped icosahedral capsid • (resistant to inactivation!)

9. II. Viral genome: circular dsDNA (At least 100 types based on DNA sequence homology: very tissue-specific) (bp) E: early genes; L: late genes

10. III. Life cycle: Tissue/cell-dependent! L1, L2 E1, E2 E6, E7

11. Tumor suppressors

12. Infection and immunity: • Transmission:direct contact, sexual contact, birth canal • Targets: skin (cutaneous HPV) or mucosa (mucosal HPV) • Major pathogenesis: warts and tumors • Local infection • Immune control: innate and cell-mediated immunity • Persistent infection and recurrence • Symptomatic and asymptomatic infection and shedding

13. L1, L2 “Persistent infection” E1, E2 • Low-level Ag expression • Immuno-privileged site E6, E7

14. Diseases: • Skin warts: HPV 1~4 (3~4 months for development) • Anogenital warts (condylomata acuminata): HPV 6, 11 • Benign tumors (oral or laryngeal papillomas): HPV 6, 11 • Cervical dysplasia and carcinoma: HPV 16, 18 • (1~4 years for development) • Anogenital or oropharyngeal cancers: HPV 16, 18

15. Warts:

16. Progression of HPV-mediated cervical carcinoma:

17. HPV DNA integration/breaking site in cervical carcinoma

18. VI. Diagnosis: • Histological examination of warts • (prickle cell hyperplasia and hyperkeratosis) • Papanicolaou-stained cervical smear (Pap smear) • (Koilocytotic cells) • Detection of HPV DNA • (PCR, in situ hybridization, sequencing/typing) • Immunodetection of viral antigens • No virus culture!

19. Koilocytosis (vacuolated cytoplasm) in Pap staining of HPV-infected cells

20. VII. Treatment and control: • Removal of warts • Induction of local inflammation • (imiquimod, interferon) • Local treatment with cidofovir • (selective killing of HPV-infected) • HPV vaccine (L1 viruslike particles of HPV 6, 11, 16, 18) • (reduction of anogenital warts and cervical cancer) • Safe sex and avoiding direct contact of infected tissues

21. Polyomaviruses BK virus and JC virus in human Simian vacuolating virus 40 (SV40) in monkey

22. Viral particle: nonenveloped capsid • II. Viral genome: circular dsDNA Early genes: For viral DNA replication Late genes: For virion assembly SV40 5 kb Large T antigen

23. Tumor suppressors

24. III. Life cycle:

25. IV. Infection: • Transmission: maybe respiratory route • Infection of lymphocytes and spread through viremia • Ubiquitous, asymptomatic and persistent infection • (infection before 15 yo) • Latency: BK in kidney; JC in kidney, B cells or myeloid cells • Reactivation during pregnancy (no effect on fetus) • or in immunocompromised patients

26. Diseases: in immunocompromised patients • BK virus: renal diseases • Ureteral stenosis or hemorrhagic cystitis • JC virus: progressive multifocal leukoencephalopathy (PML) • Partial transformation of astrocytes (glioblastoma-like) • Lysis of oligodendrocytes (demyelination) • 10% of AIDS patients, dying within 2 years • No human cancer

27. Immunocompromised

28. Diagnosis: • PML: brain lesions with demyelination in white matter • PCR detection of viral DNA in urine or cerebrospinal fluid • Immunodetection of viral antigens in affected tissues • Urine cytologic test: enlarged cells with basophilic inclusions • No virus isolation • VII. Treatment and control? • Prevention from immunosuppression

29. Adenoviruses

30. Viral particle: nonenveloped icosadeltahedral capsid • (resistant to drying, detergents, protease, acid, mild chlorine) Penton bases with fibers: • Viral attachment to cell receptors • (Receptor: CAR) • Virus entry through endocytosis • (Coreceptor: integrin αvβ3/αvβ5) • Serotype-specific antigens • Inhibition of host mRNA transport • and protein synthesis

31. II. Viral genome: linear dsDNA with 5’ terminal protein

32. Tumor suppressors

34. /PKR • E3 19 kD protein reduces MHC class I to prevent antigen presentation. • E3 14.7 kD protein inhibits TNF-a production.

35. III. Life cycle: • In permissive cells: • Viral replication, cell death with virion production • In nonpermissive cells: • Latency with viral genomes in the nuclues • Cell transformation in rodent cells

36. Infection and immunity: • Transmission:aerosol, close contact, fecal-oral routes • Primary targets: mucoepithelial cells (serotype-dependent) • Major pathogenesis: cell lysis and tissue damage • Local infection and spread through viremia • Immune control: antibody and cell-mediated immunity • Persistent infection in lymphoid tissues • Symptomatic and asymptomatic infection and shedding

37. Oral route

38. Diseases: • Children (<14 yo) and people in crowded areas are at risk. • Immunocompromised patients may have more serious diseases • No human cancer (Ad 1, 2, 5, 6) (Ad 4, 7) (Ad 40-42)

39. Adenovirus respiratory infection

40. VI. Diagnosis: • Virus isolation from affected tissues • (culture in epithelial cells, ~ 6 days) • Detection, typing, and grouping by immunoassay or PCR • VII. Treatment and control: • No approved treatment for adenovirus infection • Live Ad 4 and 7 vaccines for military recruits • Careful handwashing and chlorination of swimming pools

41. Adenoviral vectors for gene delivery:

42. Generation of adenoviral vectors: E1 Advantages? Disadvantages?

43. 6/10 6/01 6/15