Human Cancer Viruses Chapter 43

Viruses Associated With Human Cancers 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

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

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

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

Retroviruses

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

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

DNA Tumor Viruses 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 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 Papillomaviruses Features Many human types 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)