Tumour Viruses

1. Tumor Viruses
Genome all viral proteins
Replication Lysis Progeny virions
Lytic Life Cycle
For most viruses:
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2. 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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3. 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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4. 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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5. • 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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6. Two Major Classes of Tumor Viruses
DNA Tumor Viruses
DNA viral genome
Host RNA
polymerase
Viral mRNA
Viral protein
DNA-dependent
DNA polymerase
(Host or viral)
Similar to host cell!
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7. RNA Tumor Viruses
Viral RNA genome
Reverse transcriptase (Virus-encoded)
Viral DNA genome (integrated)
DNA-dependent RNA polymerase (Host Host
RNA pol II)
Viral genomic RNA
Splicing (Host splicing enzymes)
messenger RNA
viral protein
Virus
Important: Use HOST
RNA polymerase
to make its genome
An enzyme that
normally
makes mRNA
IMPORTANT
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8. 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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9. 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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10. DNA Tumor Viruses In
Human Cancer
Papilloma Viruses
• Epidermodysplasia verruciformis
wart
malignant
squamous cell carcinoma
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11. DNA Tumor Viruses In
Human Cancer
Epidermodysplasia
verruciformis
Papilloma virus
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12. 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 All histologically similar
Lung
10% of human cancers may be HPV-linkedwww.freelivedoctor.com

13. 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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14. Papilloma Viruses
•The important transforming genes in
papilloma viruses are: E6 and E7
•Early genes - Not encoding structural
proteins
•Oncogenes
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15. 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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16. 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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17. 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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18. 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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19. 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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20. 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
Kaposi’s sarcoma
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21. DNA Tumor Viruses In
Human Cancer
Hepatitis B Virus
DNA genome
RNA polymerase II
RNA Provirus
Reverse transcriptase
DNA genome
Host enzyme
Viral enzyme
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22. 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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23. 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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24. 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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25. 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
virus
virus
host
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26. RNA Tumor
Viruses
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27. 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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28. 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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29. RNA Tumor Viruses
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30. 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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31. 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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32. 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 www.freelivedoctor.com

33. 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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34. RNA Tumor Viruses
Retrovirus Life Cycle
Endocytosis
Fusion of membranes
Release of nucleocapsid to cytoplasm
Nucleus
Bind to
surface receptor
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35. 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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36. 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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37. primer
Viral
genomicRNA
Reverse
transcriptase
dsDNA
promotor
RNA synthesis
initiation site
RNA pol II
RNA synthesis termination
site
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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38. ?
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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39. RNA Tumor Viruses
Clue: Difference in the two forms
RNA
R U5 GAG POL ENV U3 R
LTR
Repeat
region
Repeat
region
DNA
U3 R U5 GAG POL ENV U3 R U5
LTR
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40. promotor
Viral RNA
Reverse
transcriptase
R U5
U3 R
U3 R U5 U3 R U5
Long terminal repeats are formed
RNA initiation site
RNA termination site
POLII
POLII
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41. Retroviruses can have only one
promotor
LTR LTR
U5
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
POLIIPOLII
Contained in U3
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42. R U5 GAG POL ENV U3 R
Rous Sarcoma Virus
R U5 GAG POL ENV U3 R
Some retroviruses have an
extra gene
“typical retrovirus”
SRC
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43. 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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44. RNA Tumor Viruses
Viral Oncogene
V-onc
Cellular Proto-oncogene
C-onc
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45. 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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46. 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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47. RNA Tumor Viruses
In contrast:
Chronically transforming retroviruses
cause tumors inefficiently after prolonged period of time
No oncogene! – How does it cause a
tumor?
R U5 GAG POL ENV U3 R
Avian Leukosis Virus (causes lymphomas)
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48. 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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49. 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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50. RNA Tumor Viruses
Could C-oncs be involved in NON-VIRAL cancers?
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51. 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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52. DNA Tumor Viruses
Herpes
Genes can be
assigned to
sites on
specific
chromosomes
mos and myc :
chromosome 8
fes: chromosome 15
fes
mos
myc
myb
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53. 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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54. 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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55. 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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56. 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
Always binds Always binds
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57. 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
Mutation growth
Heterozygote Homozygote
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58. Anti-Oncogenes
Retinoblastoma gene has normal
regulatory function in many cells
Involved in
Retinoblastoma
Lung carcinomas
Breast carcinomaswww.freelivedoctor.com

59. Anti-Oncogenes
P53
Inactivated by
• deletion
• point mutation
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60. 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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61. Anti-Oncogenes
Rb Gene
Rb
Rb
protein
Rb
Stops replication
Rb
Adenovirus E1A
Cell cycle continues
Retinoblastoma
105kD
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62. Anti-Oncogenes
p53
P53 gene
P53 gene P53 gene
P53
P53 DNA
Stops replication
Hepatitis C
P53
replication replication
Papilloma
proteolysis
P53
Papilloma
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