Transcript 17 Cancer viruses

Human Cancer
Viruses
Chapter 43
Viruses Associated With Human
Cancers
Family
Virus
Cancer
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
Papillomavirida
e
General Features of Viral
Carcinogenesis
• Most are DNA viruses (exceptions: some retroviruses and
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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
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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
• Persistent infections
• All known human tumorHosts
viruses establish persistent infections
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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
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EBV infects B cells
HTLV infects T cells
Retroviruses
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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
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reverse transcriptase
protease
envelope
gag
tax
rex
Genes encoded in both directions
Retroviruses
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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
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Recombination activation genes 1 & 2 that rearrange antibody and T cell
receptor genes
Classification
Leukemia viruses
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Alpharetrovirus
Gammaretrovirus
Nontransforming retroviruses
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Deltaretrovirus
Lentivirus
Mechanisms of Retroviral
Carcinogenesis
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Infection leads to uncoating in the cytoplasm
Reverse transcriptase makes a double-stranded DNA copy
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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
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This version of the viral genome is termed the provirus
Two replication strategies
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Induce cell division - leads to copies of the viral genome in each daughter cell
Productive infection - spread of virus to other cells
Tax
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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
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
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DNA Tumor Viruses
Papillomaviruses
Features
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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
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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
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HeLa cells are cervical cancer cells from Helen Lang (fatal)