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Human Cancer Viruses

Human Cancer Viruses. Chapter 43. Family. Virus. Cancer. Papillomaviridae. Human papillomaviruses. Genital tumors Squamous cell carcinomas Oropharyngeal carcinomas. Herpesviridae. Epstein-Barr virus. Nasopharyngeal carcinoma African Burkitt’s lymphoma B cell lymphoma. Hepadnaviridae.

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Human Cancer Viruses

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  1. Human Cancer Viruses • Chapter 43

  2. Family Virus Cancer Papillomaviridae Human papillomaviruses Genital tumors Squamous cell carcinomas Oropharyngeal carcinomas Herpesviridae Epstein-Barr virus Nasopharyngeal carcinoma African Burkitt’s lymphoma B cell lymphoma Hepadnaviridae Hepatitis B virus Hepatocellular carcinoma Retroviridae Human T lymphotrophic viruses Human immunodeficiency viruses Adult T cell leukemias AIDS-associated tumors (due to impaired T cell responses Flaviviridae Hepatitis C virus Hepatocellular carcinoma Viruses Associated With Human Cancers

  3. General Features of Viral Carcinogenesis • Most are DNA viruses (exceptions: some retroviruses and flaviviruses) • Influence the cell cycle by • Encoding proteins that direct cell cycle progression • Integrating near cellular genes that control cell cycle progression • The Central Tenets of Viral Carcinogenesis • Viruses can cause cancers in humans and animals • Tumor viruses frequently establish persistent infections • Host susceptibility factors are important determinants • Viruses are seldom carcinogenic on their own • Virus infections are far more common than viral cancers • Prolonged periods (years) are usually required for viral carcinogenesis • Viral strains may be different in their capacity to cause cancers • Cancer viruses modulate cell cycle progression • Animal models can reveal mechanisms of viral carcinogenesis • Viral markers are usually present in in cancerous cells • One virus species can be associated with multiple tumor types

  4. Interactions of Tumor Viruses With Their Hosts • Persistent infections • All known human tumor viruses establish persistent infections • Genetic differences in individuals results in differential susceptibilities • Host immune response • Persistent viruses must evade the host immune response • Different viruses have evolved different evasion mechanisms • Mechanisms of action by human cancer viruses • Viral gene is able to subvert cell cycle control • Viruses alter the expression of normal cell cycle progression genes • Either results in cellular transformation into an oncogenic state • Cell susceptibility to virus • Tumor viruses possess cell specificity and do not infect other cells • EBV infects B cells • HTLV infects T cells • Retention of viral nucleic acid in a cell • Viral genes are always present in the transformed cells

  5. Retroviruses • Structure and composition • Diploid single-stranded RNA viruses (5-8 kb) • Helical ribonucleoprotein • Icosahedral symmetry (100 nm) • Enveloped • Genetics • Only diploid viruses • Nonsegmented • About 10 genes, 16 proteins • reverse transcriptase • protease • envelope • gag • tax • rex • Genes encoded in both directions

  6. Retroviruses

  7. Retroviruses • Epidemiology • Typical infectious viruses (exogenous) • Sexual transmission • IV drug abusers • Other, unknown transmission mechanisms • Germline (endogenous) • High degree of similarity to retrotransposons • Some are required for normal functions • Recombination activation genes 1 & 2 that rearrange antibody and T cell receptor genes • Classification • Leukemia viruses • Alpharetrovirus • Gammaretrovirus • Nontransforming retroviruses • Deltaretrovirus • Lentivirus

  8. Mechanisms of Retroviral Carcinogenesis • Infection leads to uncoating in the cytoplasm • Reverse transcriptase makes a double-stranded DNA copy • An RNA-dependent DNA polymerase • A DNA-dependent DNA polymerase • A DNA-dependent RNA polymerase • The ds-DNA translocates into the nucleus where it randomly integrates in host cell chromosome • This version of the viral genome is termed the provirus • Two replication strategies • Induce cell division - leads to copies of the viral genome in each daughter cell • Productive infection - spread of virus to other cells • Tax • Transcription factor • Dimerizes with cellular activating transcription factor-4 (ATF4) • The dimer binds to HTLV proviral and cellular promoters to drive cell division

  9. Virus Viral Oncoproteins Cellular Targets Polyomavirus SV40 Large T antigen Small t antigen p53 and pRb tumor suppressor genes PP2A Human papillomavirus E6 E7 p53, DLG, MAGI-1, MUPP1 pRb Bovine papillomavirus E5 PDGFβ receptor Adenovirus E1A E1B-55k pRb p53 Adenovirus 9 E4ORF1 DLG, MAGI-1, MUPP1 Epstein-Barr virus LMP1 vIL10 BCL2 homolog TRAFs IL-10 receptor (soluble viral cytokine) Rescues cell from apoptosis DNA Tumor Viruses

  10. DNA Tumor Viruses • Papillomaviruses • Features • Nonenveloped icosahedral (55 nm) • Circular ds-DNA (8 kb) • Nuclear replication • Stimulate cellular DNA synthesis • Highly restricted host range and tissue range • Many human types • Only a few are known to cause cancers • Cervical cancer is the most important • Vaccine is now available (Gardasil; types 6, 11, 16, 18) • Cause warts (abnormal cellular proliferation) • Replicate in basal stem cells and keratinocytes of the skin and mucosa • HeLa cells are cervical cancer cells from Helen Lang (fatal)

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