Tumor Viruses

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Tumor Viruses
For most viruses
Replication Lysis
Progeny virions
Lytic Life Cycle
Genome all viral proteins
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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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Tumor Viruses
TRANSFORMATION
VIRAL TRANSFORMATION The changes in the
biological functions of a cell that result from
REGULATION of the cells metabolism by viral
genes and that confer on the infected cell
certain properties characteristic of NEOPLASIA
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Tumor Viruses

• 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

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Similar to host cell!
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IMPORTANT
Important Use HOSTRNA polymerase to make its
genome
An enzyme that normallymakes mRNA
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DNA Tumor Viruses
DNA genome mRNA protein virus
Host RNA polymerase II
Host enzymes
OR TRANSFORMATIONIn 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
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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
• gt100 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

Possible association of BK with human prostate
cancer
Polyoma virus transforms cells when the genome is
incomplete
Early functions are necessary - ONCOGENES
JC PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
(PML)
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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
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
Epstein-Barr Virus

• Burkitts Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis (glandular fever)
• Transforms human B-lymphocytes in vitro

• Burkitts lymphoma malarial infested regions
• Nasopharyngeal cancer China, SE Asia diet?

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DNA Tumor Viruses In Human Cancer
Human herpes virus 8 Kaposis 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 CancerHepatitis 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 CancerHepatitis 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

• Can transform cells or have lytic life cycle

• Often integrate into host genome

• In transformation often ONLY early genes 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
A normal retrovirus has 3 genes
GAG internal proteins
ENV Envelope glycoproteins
POL Enzymes Reverse transcriptase RNase
H Integrase Protease
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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
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

• Also causes Tropical spastic paraparesis
• (affects the gray and white matter of the spinal
  cord - myelopathy)
• 1-4 of infected people

Immunosuppression
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RNA Tumor Viruses
Retroviruses known to cause human cancer

• 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)

Seroprevalence in these populations gt 20 Women
over 50 seroprevalence - up to 50 in some
populations

• HIV ?

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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 DNA polymerase
Host splicing enzymes
Host RNA pol II

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RNA Tumor Viruses
Drawback to this lifestyle Genomic
RNA DNA Genomic RNA
Reverse transcriptase
Host RNA pol II
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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Problem of using RNA pol II to copy a gene
Viral genomicRNA
RT
primer
Reverse transcriptase
dsDNA
Result New copy of viral RNA is shorter - lacks
control sequences
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RNA Tumor Viruses
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

?
Perhaps virus could integrate downstream of a
promotor etc so that the cell provides sequences
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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R U5
Viral RNA
U3 R
Reverse transcriptase
U3 R U5
U3 R U5
Long terminal repeats are formed
POLII
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Retroviruses can have only one promotor
Contained in U3
LTR
LTR
POLII
Therefore only one long RNA can be made Therefore
mRNA requires processing Explains why RNA has to
be positive sense
U5
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Some retroviruses have an extra gene
typical retrovirus
R U5 GAG POL ENV
U3 R
SRC
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Some retroviruses have an oncogene instead of
their regular genes
Avian Myeloblastosis Virus
R U5 GAG POL MYB U3
R
Feline Sarcoma Virus (FSV)
R U5 dGAG FMS dENV
U3 R
Avian Myelocytoma Virus (MC29)
R U5 dGAG MYC
dENV U3 R
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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 cells 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
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)

• Suggests tumor arose from one cell
• Something must be important about this site for
  transformation
• Crucial event must be rare

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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 VirusesHerpes
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
Burkitts Lymphoma 814 translocation Break in
chromosome 14 at q32
myc
Acute myelocytic leukemia715918111517
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Oncogenesis by rearrangement
Tumor c-onc new promotor Burkitts
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
Dominant mutations
Heterozygote
Homozygote
Allele 1 Allele 2 Allele 1
Allele 2 Normal Mutant
Mutant Mutant
Binds under special circumstances
Mutant always binds
Mutant always binds
Mutant always binds
Function gained
Function gained
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Anti-Oncogenes
Recessive mutations
Rb Gene
Mutant Rb
Mutant Rb
Mutant Rb
Rb
Rb protein
Heterozygote
Homozygote
Function lost
Rb
Binds and controls cell cycleTurns off DNA
replication
No binding - Growth continues
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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 VirusesOncogenes

• 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
Retinoblastoma
Adenovirus E1A
Rb Gene
Rb protein
Rb
105kD
Rb
Rb
Cell cycle continues
Stops replication
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Anti-Oncogenes
p53
P53 gene
P53 gene
P53 gene
Papilloma
Hepatitis C
P53
P53
P53
Papilloma proteolysis
P53
DNA
Stops replication
replication
replication