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  1. 1.
  2. 2. Papillomaviruses
  3. 3. Classification <ul><li>Widespread in nature, infecting many vertebrates </li></ul><ul><li>Highly species specific </li></ul><ul><li>100 + HPV types, classified basis on nucleic acid homology </li></ul>
  4. 4. Human papillomavirus infections <ul><li>Transmission </li></ul><ul><ul><li>Direct contact with broken skin or mucosa </li></ul></ul><ul><li>Skin warts </li></ul><ul><li>Genital tract HPV's </li></ul><ul><li>Mucosal HPV's </li></ul><ul><li>Various HPV types show tissue specificity </li></ul>
  5. 5. HPV and skin warts
  6. 6. Papillomavirus disease
  7. 7. Clinical genital tract and mucosal HPV’s
  8. 8.
  9. 9. HPV16 genome Genomic map of HPV-16. The genome is a double-stranded circular DNA molecule of 7904 base pairs. Transcription occurs in a clockwise manner; the only transcriptional promoter presently mapped for HPV-16 is designated P97. The open reading frames deduced from the DNA sequence are designed E1 to E7, L1, and L2 and are indicated outside of the circular genome. AE and AL represent the early and late polyadenylation sites. The viral long control region (LCR) contains transcriptional and replication regulatory elements.
  10. 10. Papilloma virus gene function
  11. 11. Papillomavirus replication and differentiation of the epidermis Differentiation of normal cutaneous squamous epithelium and papillomaviral activities in productively infected benign lesions. The various epithelial strata and the host-differentiation, stage-specific, gene-expression profile are indicated in the left and center panels.
  12. 12. Replication cycle of a papillomavirus. To establish a wart or papilloma, the virus must infect a basal epithelial cell. Our knowledge is limited about the initial steps in the replication cycle such as attachment (1), uptake (2), endocytosis (3), and transport to the nucleus and uncoating of the viral DNA (4). Early-region transcription (5), translation of the early proteins (6), and steady-state viral DNA replication (7) all occur in the basal cell and in the infected suprabasal epithelial cell. Events in the viral life cycle leading to the production of virion particles occur in the differentiated keratinocyte: vegetative viral DNA replication (8), transcription of the late region (9), production of the capsid proteins L1 and L2 (10), assembly of the virion particles (11), nuclear breakdown (12), and release of virus (13). (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Fig. 65-6.) Papillomavirus replication
  13. 13. Papillomavirus pathogenesis
  14. 14. Cervical HPV infection Natural history of cervical HPV infection. Approximate number of US cases of the different categories of infeciton. Most subclinical infections and low-grade dysplasias regress spontaneously. Even high-grade dysplasia has some potential to regress spontaneously. Infection with HPV-16 or HPV-18 represents a minority of the subclinical infections and low-grade dysplasias, whereas they represent most of the high grade dysplasias and invasive cancers.
  15. 15. Progression from benign cervical condylomatous liesion to invasive carcinoma. Infection by oncogenic HPV types, especially HPV16, may directly cause a benign condylomatous lesion, low-grade dysplasia, or sometimes even an early high-grade lesion. Carcinoma in situ rarely occurs until several years after infection. It results from the combined effects of HPV genes, particularly those encoding E6 and E7, usually after integration of the viral DNA into the host DNA and a series of genetic and epigenetic changes in cellular genes. HSIL, high-grade squamous intraepithelial lesion, LSIL, low-grade squamous intraepithelial lesion; CIN, cervical intraepithelial neoplasia. HPV and cervical dysplasia
  16. 16. Low-grade squamous intraepithelial lesions of the cervix. A: Histologic section showing koilocytes with vacuolated cytoplasm and parakeratosis (H&E, *234). B: The darkly stained nuclei contain papillomavirus capsid antigen. [Immunoperoxidase stained with genus-specific antiserum (H&E, *234)]. C: Cervical smear. The squamous epithelial cells are rounded. They occur in clumps and display koilocytic changes (Papanicolaou stain; H&E *375). D: Cervical smear. The darkly stained nuclei contain papilloamavirus capsid antigen. (Immunoperoxidase staind with genus-specific antiserum; H&E, *750). Cervical dysplasia
  17. 17. Papanicolaou stain of the exfoliated cervicovaginal squamous epithelial cells showing the perinuclear cytoplasmic vacuolization, termed koilocytosis (vacuolated cytoplasm), which is characteristic of human papillomavirus infection. Papillomavirus cytology
  18. 18. Correlation between HPV type, integration, and histology
  19. 19. Structure of the single copy of HPV-16 DNA integrated into the SiHa cell line derived from a cervical carcinoma. The jagged line represents human chromosomal sequences; the nucleotide numbers pertain to the integrated HPV-16 genome. The open boxes indicate the early and late open reading frames (ORFs). Integration has occurred in the E2 ORF, and a portion of the E2 ORF has been deleted. (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001Fig. 66-9.) HPV DNA integration into a human chromosome <ul><li>Integration leads to up-regulation of E6 and E7 </li></ul><ul><ul><li>Inactivation of E2 </li></ul></ul><ul><ul><li>Host transcription elements </li></ul></ul><ul><ul><li>Host sequences stabilize mRNA </li></ul></ul>
  20. 20. Diagnosis <ul><li>Pathology, cytology </li></ul><ul><li>Immunohistochemistry </li></ul><ul><li>Nucleic acid </li></ul><ul><ul><li>Hybridization (Southern, in situ), PCR </li></ul></ul><ul><ul><li>Identification of specific HPV type can assist in evaluating prognosis and treatment </li></ul></ul><ul><ul><li>Integration state? </li></ul></ul>
  21. 21. Prevention/Treatment <ul><li>Recombinant virus-like particle vaccines </li></ul><ul><ul><li>Gardasil </li></ul></ul><ul><ul><ul><li>FDA approved; HPV 16, 18, 6, 11 </li></ul></ul></ul><ul><ul><li>Cervarix </li></ul></ul><ul><ul><ul><li>FDA approval pending; HPV 16, 18 </li></ul></ul></ul><ul><li>Pap smear </li></ul><ul><li>Surgery </li></ul>
  22. 22. Summary: human papillomavirus <ul><li>Structure </li></ul><ul><ul><li>Small (8 kb) circular dsDNA genome, naked capsid </li></ul></ul><ul><li>Pathogenesis </li></ul><ul><ul><li>transmission by direct contact or sexual; skin, mucosa </li></ul></ul><ul><ul><li>replication in nucleus of basal cells of epithelium; very host dependent; coupled to epithelial differentiation </li></ul></ul><ul><ul><li>no spread </li></ul></ul><ul><ul><li>primarily cellular immune response </li></ul></ul><ul><ul><li>transforming infection; warts are tumors; cervical carcinoma </li></ul></ul><ul><li>Diagnosis </li></ul><ul><ul><li>cytology (PAP smear; koilocytosis) </li></ul></ul><ul><ul><li>immunohistochemistry </li></ul></ul><ul><ul><li>nucleic acid </li></ul></ul><ul><li>Prevention/treatment </li></ul><ul><ul><li>recombinant subunit (VLP) vaccine </li></ul></ul><ul><ul><li>PAP smear </li></ul></ul><ul><ul><li>surgery </li></ul></ul>