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Tumor Viruses (Examville.com)

Tumor Viruses (Examville.com)

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Download this presentation at www.Examville.com Learn and review on the go! Use Quick Review Medical Notes to help you learn or brush up on the subject quickly. You can use the review notes as a reference, to understand the subject better and improve your grades.
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Tumor Viruses
For most viruses:
Replication Lysis Progeny virions

Lytic Life Cycle
Genome all viral proteins

Tumor Viruses
Virus

Latent Life Cycle

Cell

Integration (often)

Transformation

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

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

Tumor Viruses
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
• 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

Two Major Classes of Tumor Viruses
DNA Tumor Viruses
DNA viral genome
DNA-dependent DNA polymerase (Host or viral) Host RNA polymerase

Viral mRNA Similar to host cell! Viral protein

RNA Tumor Viruses
Viral RNA genome
Reverse transcriptase (Virus-encoded)

Viral DNA genome (integrated) IMPORTANT
DNA-dependent RNA polymerase (Host RNA pol II)

Viral genomic RNA
Splicing (Host splicing enzymes)

messenger RNA

viral protein

Important: Use HOST RNA polymerase to make its genome An enzyme that normally makes mRNA

Virus

DNA Tumor Viruses
DNA genome
Host RNA polymerase II

mRNA
Host enzymes

protein

virus OR TRANSFORMATION In transformation usually only EARLY functions are expressed

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

DNA Tumor Viruses In Human Cancer
Papilloma Viruses • Epidermodysplasia verruciformis

wart

malignant squamous cell carcinoma

DNA Tumor Viruses In Human Cancer
Papilloma Viruses urogenital cancer wart malignant squamous cell carcinoma
Papilloma viruses are found in 91% of women with cervical cancer

Squamous cell carcinoma: Larynx Esophagus Lung

All histologically similar

10% of human cancers may be HPV-linked

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)

Papilloma Viruses
• The important transforming genes in papilloma viruses are: E6 and E7 • Early genes - Not encoding structural proteins • Oncogenes

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)

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

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

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”

DNA Tumor Viruses In Human Cancer
Epstein-Barr Virus
• 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?

DNA Tumor Viruses In Human Cancer
Human herpes virus – 8 Kaposi’s Sarcoma Herpes Virus
Kaposi’s sarcoma
Hematologic malignancies • Primary effusion lymphoma
• Multicentric Castleman's disease (MCD) – a rare lymphoproliferative disorder (AIDS) • MCD-related immunoblastic/plasmablastic lymphoma • Various atypical lymphoproliferative disorders

DNA Tumor Viruses In Human Cancer
Hepatitis B Virus
DNA genome
RNA polymerase II

Host enzyme

RNA Provirus
Reverse transcriptase Viral enzyme

DNA genome

DNA Tumor Viruses In Human Cancer
Hepatitis B continued • Vast public health problem

• 10% of population in underdeveloped countries are chronic carriers

•Long latency

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

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

RNA Tumor Viruses
RNA Genome - Retroviruses
RNA-dependent DNA Polymerase encoded by virus REVERSE TRANSCRIPTASE RNA genome
Reverse transcriptase
virus

DNA genome
Integrase
virus

Integrates
Host RNA polymerase II
host

RNA genome

RNA Tumor Viruses
A normal retrovirus has:
3 genes GAG : internal proteins ENV: Envelope glycoproteins POL: Enzymes
Reverse transcriptase – RNase H Integrase Protease

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

RNA Tumor Viruses

RNA Tumor Viruses
Groups of Retroviruses
• Oncovirinae • Lentiviruses Long latent period
important

Tumor viruses and similar
important

Progressive chronic disease
Visna HIV

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)

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

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 > 20% Women over 50: seroprevalence - up to 50% in some populations

• HIV ?

RNA Tumor Viruses
Retrovirus Life Cycle
Bind to surface receptor Endocytosis

Fusion of membranes

Release of nucleocapsid to cytoplasm

Nucleus

RNA Tumor Viruses
Parental RNA
Reverse transcriptase

RNA/DNA Hybrid
Reverse transcriptase

Linear DNA/DNA duplex

Circular Duplex DNA
Integrase
Host DNA polymerase

Integration
Host RNA pol II

Replication (DNA genome in cell)
Host splicing enzymes

Transcription

Viral RNA genome

mRNA

protein

RNA Tumor Viruses
Drawback to this lifestyle Genomic RNA Reverse transcriptase

DNA

Host RNA pol II
Genomic RNA 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

Problem of using RNA pol II to copy a gene
RT primer

Viral genomicRNA Reverse transcriptase dsDNA

RNA synthesis initiation site
promotor

RNA pol II RNA synthesis termination site

Result: New copy of viral RNA is shorter - lacks control sequences

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!

?

RNA Tumor Viruses
Repeat region

Clue: Difference in the two forms
RNA

Repeat region

R

U5

GAG

POL
DNA

ENV

U3

R

U3

R LTR

U5

GAG

POL

ENV U3

R LTR

U5

R

U5

Viral RNA

U3

R
Reverse transcriptase

U3 promotor
POLII

R

U5

U3

R

U5

Long terminal repeats are formed
POLII

RNA initiation site

RNA termination site

Retroviruses can have only one promotor
Contained in U3

LTR
POLII

LTR
POLII

RNA initiation site

RNA termination site

Therefore only one long RNA can be made
Therefore mRNA requires processing Explains why RNA has to be positive sense U5

Some retroviruses have an extra gene

“typical retrovirus”

R

U5

GAG

POL

ENV

U3

R

Rous Sarcoma Virus
R U5 GAG POL ENV SRC U3 R

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

RNA Tumor Viruses
Viral Oncogene
V-onc

Cellular Proto-oncogene
C-onc

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

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

RNA Tumor Viruses
In contrast:

Chronically transforming retroviruses
cause tumors inefficiently after prolonged period of time
Avian Leukosis Virus (causes lymphomas)

R

U5

GAG

POL

ENV

U3

R

No oncogene! – How does it cause a tumor?

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

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

RNA Tumor Viruses

Could C-oncs be involved in NON-VIRAL cancers?

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

DNA Tumor Viruses Herpes
Genes can be assigned to sites on specific chromosomes

myb

mos myc

mos and myc : chromosome 8
fes

fes: chromosome 15

Cancers often result from gene translocations Burkitt’s Lymphoma
8:14 translocation Break in chromosome 14 at q32

myc

Acute myelocytic leukemia 7:15 9:18 11:15:17

Oncogenesis by rearrangement
Tumor
Burkitt’s lymphoma
B-cell chronic lymphocytic
leukemia T cell chronic lymphocytic

c-onc
myc
bcl-1
bcl-2 tcl-1
(8)

new promotor
Ig heavy (8 to 14) Ig light (8 to 2)
Ig heavy (11 to 14)
Ig heavy (18 to 14) T cell receptor

leukemia
T cell chronic lymphocytic leukemia myc

(14 inversion)
T cell receptor (8 to 14)

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

Proto-oncogenes
Heterozygote Allele 1 Normal Allele 2 Mutant

Dominant mutations

Homozygote Allele 2 Mutant

Allele 1 Mutant

Binds under special circumstances

Mutant always binds

Mutant always binds

Mutant always binds
Always binds

Always binds

Function gained

Function gained

Anti-Oncogenes
Recessive mutations Mutation Rb Gene Mutant Rb growth Mutant Rb Mutant Rb

Rb
Rb protein

Heterozygote Rb
Binds and controls cell cycle
Turns off DNA replication

Homozygote Function lost
No binding - Growth continues

Anti-Oncogenes
Retinoblastoma gene has normal regulatory function in many cells

Involved in
Retinoblastoma Lung carcinomas Breast carcinomas

Anti-Oncogenes
P53
Inactivated by • deletion • point mutation

DNA Tumor Viruses Oncogenes
• Adenovirus • SV 40 • Polyoma • BK virus • Lymphotropic virus • Human papilloma Virus-16 E1A region 2 Large T Large T Large T Large T E6, E7

All have a sequence in common Mutations in this region abolish transformation capacity

Anti-Oncogenes
Retinoblastoma Rb Gene Adenovirus E1A

Rb protein

Rb

105kD Rb

Rb

Stops replication

Cell cycle continues

Anti-Oncogenes
p53
P53 gene

P53 gene
Hepatitis C

P53 gene
Papilloma

P53

P53

P53

Papilloma proteolysis
P53 DNA

Stops replication

replication

replication

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