1. Human Cancer Viruses
Chapter 43

2. 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

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. 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

10. 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)