Tumor Viruses

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Tumor Viruses
Genome all viral proteins
Replication Lysis Progeny virions
Lytic Life Cycle
For most viruses:
Non-structural and structural proteins made
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Tumor Viruses

Virus

Cell

Integration (often)

Transformation
Latent Life Cycle
Some virus-specific proteins expressed (early functions) - No mature virus
Viral structural proteins are not expressed
Changes in the properties of host cell - TRANSFORMATION
Sometimes latency may terminate – cell must be infected by complete virus
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Tumor Viruses
Transformation:
Loss of growth control
Reduced adhesion
Motility
Invasion
Ability to form tumors - viral genes interfere with control of cell replication and other aspects of the cell phenotype
Transformed cells frequently exhibit chromosomal aberrations
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TRANSFORMATION
VIRAL TRANSFORMATION
The changes in the biological functions of a cell that result from
REGULATION
of the cell’s metabolism by viral genes and that confer on the infected cell certain properties characteristic of
NEOPLASIA
Tumor Viruses
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Both DNA and RNA tumor viruses can transform cells

Integration of viral genome into the host chromosomes often occurs

Similar mechanisms of transformation by each type of tumor virus
Tumor Viruses
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Similar to host cell!
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Important: Use HOST
RNA polymerase
to make its genome
An enzyme that normally
makes mRNA
IMPORTANT
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DNA Tumor Viruses
DNA genome

mRNA

protein

virus
Host RNA polymerase II
Host enzymes
OR TRANSFORMATION
In transformation usually only EARLY functions are expressed
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DNA Tumor Viruses In Human Cancer

Papilloma Viruses
cause natural cancers in animals
cause benign warts
ubiquitous
epitheliotropic - most human tumors are malignancies of epithelial cells
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DNA Tumor Viruses In Human Cancer

Papilloma Viruses

Epidermodysplasia verruciformis

wart
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DNA Tumor Viruses In Human Cancer
Epidermodysplasia
verruciformis

Papilloma virus
© 2008 Dermatology Online Journal
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DNA Tumor Viruses In Human Cancer

Squamous cell carcinoma:
Larynx
Esophagus All histologically similar
Lung
10% of human cancers may be HPV-linked
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DNA Tumor Viruses In Human Cancer

Papilloma Viruses
>100 types identified - most common are types 6 and 11
Most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of penile cancers)
EPIDEMIOLOGIAL STUDIES BUT:
HPV 16 and HPV 18 do transform human keratinocytes
Effective Vaccine
(quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in yeast - Gardasil)
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Papilloma Viruses
The important transforming genes in papilloma viruses are: E6 and E7
Early genes - Not encoding structural proteins
Oncogenes
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DNA Tumor Viruses In Human Cancer

Polyoma Viruses
Simian virus 40 - juvenile hamster sarcomas, transformation
Polyoma - mouse leukemia, in vitro transformation
Human polyomas (JC and BK) - monkey sarcoma, transformation
Early functions are necessary - ONCOGENES
JC: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)
Possible association of BK with human prostate cancer
Polyoma virus transforms cells when the genome is incomplete
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DNA Tumor Viruses In Human Cancer

Adenoviruses
Highly oncogenic in animals
Only part of virus integrated
Always the same part
Early functions

E1A region: 2 T antigens
E1B region: 1 T antigen
E1A and E1B = Oncogenes
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DNA Tumor Viruses In Human Cancer

Common pattern

Early functions (non-structural) proteins are involved in transformation

Papilloma: E6 and E7
Polyoma: Large T and small T antigen
Adenovirus: E1A and E1B
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DNA Tumor Viruses In Human Cancer

ONCOGENE
A gene that codes for a protein that potentially can transform a normal cell into a malignant cell
An oncogene may be transmitted by a virus in which case it is known as a VIRAL ONCOGENE
v-onc
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DNA Tumor Viruses In Human Cancer

Herpes Viruses
Considerable evidence for role in human cancer
Some very tumorigenic in animals
Integrated viral DNA found in small proportion of tumor cells:
“hit and run”
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DNA Tumor Viruses In Human Cancer

Burkitt’s Lymphoma
Nasopharyngeal cancer
Infectious mononucleosis (glandular fever)
Transforms human B-lymphocytes in vitro
Burkitt’s lymphoma: malarial infested regions
Nasopharyngeal cancer: China, SE Asia – diet?
Epstein-Barr Virus
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DNA Tumor Viruses In Human Cancer

Human herpes virus – 8
Kaposi’s Sarcoma Herpes Virus
Hematologic malignancies

Primary effusion lymphoma
Multicentric Castleman`s disease (MCD) – a rare lymphoproliferative disorder (AIDS)
MCD-related immunoblastic/plasmablastic lymphoma
Various atypical lymphoproliferative disorders
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DNA Tumor Viruses In Human Cancer

Host enzyme
Viral enzyme
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DNA Tumor Viruses In Human Cancer
Hepatitis B continued


Vast public health problem
10% of population in underdeveloped countries are chronic carriers
Long latency
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DNA Tumor Viruses In Human Cancer
Hepatitis B continued

Epidemiology:
Strong correlation between HBV and hepatocellular carcinoma
China: 500,000 - 1 million new cases of hepatocellular carcinoma per year
Taiwan: Relative risk of getting HCC is 217 x risk of non-carriers
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DNA Tumor Viruses In Human Cancer

Summary
These viruses can transform cells or have lytic life cycle
Often integrate into host genome
In transformation often ONLY early genes
(non-structural) are transcribed
These are genes that are also necessary for a PRODUCTIVE infection
True viral genes
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RNA Tumor Viruses

RNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus
REVERSE TRANSCRIPTASE
RNA genome
Reverse transcriptase
DNA genome
Integrase
Integrates
Host RNA polymerase II
RNA genome
host
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RNA Tumor Viruses
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RNA Tumor Viruses
POL: Enzymes
Reverse transcriptase – RNase H
Integrase
Protease
A normal retrovirus has:
3 genes
GAG : internal proteins
ENV: Envelope glycoproteins
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RNA Tumor Viruses
RNA is:
Diploid Capped and polyadenylated
Positive sense (same as mRNA)
Viral RNA cannot be read as mRNA
(even though same sense)
New mRNA must be made
Virus must make negative sense DNA before proteins are made
Therefore virus must carry REVERSE TRANSCRIPTASE into the cell
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RNA Tumor Viruses
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RNA Tumor Viruses
Groups of Retroviruses
Oncovirinae
Tumor viruses and similar
Lentiviruses
Long latent period
Progressive chronic disease
Visna HIV
important
important
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RNA Tumor Viruses
Retroviruses known to cause human cancer
Human T cell lymphotropic virus -1 (HTLV-1)
Adult T cell leukemia, Sezary T-cell leukemia
Africa, Caribbean
S. America (Peru, Bolivia)
Some Japanese Islands
Okinawa, Kiyushu, Shikoku (12 - 16% infection rate)
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RNA Tumor Viruses
Also causes: Tropical spastic paraparesis
(affects the gray and white matter of the spinal cord - myelopathy)
1-4% of infected people
Human T cell lymphotropic virus -1 (HTLV-1)
UNITED STATES AND OTHER WESTERN COUNTRIES
IV DRUG USERS
US rate of infection about one tenth of that of HIV
BUT half as prevalent as HIV in IV drug users
Immunosuppression
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RNA Tumor Viruses
Human T cell lymphotropic virus -2 (HTLV-2)
Hairy cell leukemia
Americas, particularly in native American populations
New Mexico (Navajo and Pueblo Indians)
Florida (Seminole Indians)
Retroviruses known to cause human cancer
HIV ?
Seroprevalence in these populations > 20%
Women over 50: seroprevalence - up to 50% in some populations
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RNA Tumor Viruses
Bind to
surface receptor
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RNA Tumor Viruses
Parental RNA

RNA/DNA Hybrid

Linear DNA/DNA duplex

Circular Duplex DNA

Integration Replication (DNA genome in cell)

Transcription Viral RNA genome mRNA protein

Reverse transcriptase
Reverse transcriptase
Integrase
Host RNA pol II
Host DNA polymerase
Host splicing enzymes
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RNA Tumor Viruses
Drawback to this lifestyle

Genomic RNA

DNA

Genomic RNA
Host RNA pol II
Reverse transcriptase
Pol II is a host enzyme that, in the uninfected cell, makes mRNA

When making mRNA, pol II does not copy entire gene to RNA
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primer
Viral genomicRNA
Reverse transcriptase
dsDNA
Result: New copy of viral RNA is shorter - lacks control sequences
Problem of using RNA pol II to copy a gene
RT
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RNA Tumor Viruses
Perhaps virus could integrate downstream of a promotor etc so that the cell provides sequences
RNA polymerase II will not copy
Upstream sequences from transcription initiation site
Promotors / Enhancers
Down stream sequences from transcription termination site
Enhancers / Poly A site / termination site
OR
Virus provides its own promotors etc
BUT not copied!
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RNA Tumor Viruses
Clue: Difference in the two forms
RNA
R U5 GAG POL ENV U3 R
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Viral RNA
Reverse transcriptase
R U5
U3 R
U3 R U5
U3 R U5
Long terminal repeats are formed
POLII
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Retroviruses can have only one promotor region

LTR
LTR
U5
Therefore only one long RNA can be made
Therefore mRNA requires processing
Explains why RNA has to be positive sense
POLII
Contained in U3
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R U5 GAG POL ENV U3 R
Some retroviruses have an extra gene
“typical retrovirus”
SRC
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Feline Sarcoma Virus (FSV)
R U5 dGAG FMS dENV U3 R
Avian Myelocytoma Virus (MC29)
R U5 dGAG MYC dENV U3 R
Avian Myeloblastosis Virus
R U5 GAG POL MYB U3 R
Some retroviruses have an oncogene instead of their regular genes
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RNA Tumor Viruses
Viral Oncogene
V-onc
Cellular Proto-oncogene
C-onc
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RNA Tumor Viruses
Proto-oncogene
A cellular (host) gene that is homologous with a similar gene that is found in a transforming virus
A cellular oncogene can only induce transformation after
mutation
some other change in the cell’s genome
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RNA Tumor Viruses
The discovery of the acutely transforming retroviruses that contain
v-oncs explains how cancers may arise as a result of infection

These viruses cause rapid cancer in animals in the laboratory
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RNA Tumor Viruses
In contrast:
Chronically transforming retroviruses
cause tumors inefficiently after prolonged period of time
No oncogene! – How does it cause a tumor?
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RNA Tumor Viruses
Suggests tumor arose from one cell
Something must be important about this site for transformation
Crucial event must be rare
ALV can integrate into the host cell genome at MANY locations
but in tumor it is always at the SAME site (or restricted number of sites)
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RNA Tumor Viruses
What is special about this site?
Myelocytoma tumors from several birds all have the oncogene close to this site
It is close to
C-myc!
Oncogenesis by promotor insertion
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RNA Tumor Viruses
Could C-oncs be involved in NON-VIRAL cancers?
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RNA Tumor Viruses
What do oncogenes encode?
Proteins that are involved in growth control and differentiation
Growth factors
Growth factor receptors
Signal transduction proteins
Transcription factors
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DNA Tumor Viruses
How they tumors depended on our knowledge of RNA tumor viruses
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DNA Tumor Viruses
Herpes
Genes can be assigned to sites on specific chromosomes
mos and myc : chromosome 8
fes: chromosome 15
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Cancers often result from gene translocations
Burkitt’s Lymphoma
8:14 translocation
Break in chromosome 14 at q32
Acute myelocytic leukemia
7:15
9:18
11:15:17
myc
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Oncogenesis by rearrangement

Tumor c-onc new promotor
Burkitt’s lymphoma myc (8) Ig heavy (8 to 14)
Ig light (8 to 2)
B-cell chronic lymphocytic bcl-1 Ig heavy (11 to 14)
leukemia bcl-2 Ig heavy (18 to 14)
T cell chronic lymphocytic tcl-1 T cell receptor
leukemia (14 inversion)
T cell chronic lymphocytic myc T cell receptor (8 to 14)
leukemia
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Oncogenes
Mutations in a proto-oncogene are dominant “gain of function” mutations
However other oncogenic genes show recessive mutations
Anti-Oncogenes
Loss of function mutations
Retinoblastoma
p53
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Proto-oncogenes
Heterozygote
Homozygote
Allele 1 Allele 2 Allele 1 Allele 2
Normal Mutant Mutant Mutant
Function gained
Function gained
Dominant mutations
Binds under special circumstances
Mutant always binds
Mutant always binds
Mutant always binds
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Anti-Oncogenes
Rb Gene
Mutant Rb
Mutant Rb
Rb
Rb
Rb protein
Binds and controls cell cycle
Turns off DNA replication
No binding - Growth continues
Mutant Rb
Recessive mutations
Function lost
Heterozygote
Homozygote
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Anti-Oncogenes
Retinoblastoma gene has normal regulatory function in many cells

Involved in
Retinoblastoma
Lung carcinomas
Breast carcinomas
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Anti-Oncogenes
P53
Inactivated by
deletion
point mutation
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DNA Tumor Viruses
Oncogenes
Adenovirus E1A region 2
SV 40 Large T
Polyoma Large T
BK virus Large T
Lymphotropic virus Large T
Human papilloma Virus-16 E6, E7

All have a sequence in common
Mutations in this region abolish transformation capacity
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Anti-Oncogenes
Rb Gene
Rb
Rb protein
Rb
Stops replication
Rb
Adenovirus E1A
Cell cycle continues
Retinoblastoma
105kD
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Anti-Oncogenes
p53
P53 gene
P53 gene
P53 gene
P53
P53
DNA
Stops replication
Hepatitis C
P53
replication
replication
Papilloma proteolysis
P53
Papilloma