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For most viruses: Genome viral proteins. Replication Lysis Progeny virions . Tumor Viruses. Life Cycles. Lytic Life Cycle Virus Infection Cell Replication Lysis Progeny. Budding Life Cycle Virus Infection Cell Replication Virus

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tumor viruses

For most viruses:

Genome viral proteins

Replication Lysis Progeny virions

Tumor Viruses
life cycles
Life Cycles

Lytic Life Cycle

Virus

Infection

Cell

Replication

Lysis

Progeny

life cycles1

Budding Life Cycle

Virus

Infection

Cell

Replication

Virus

Integration of viral chromosome into the host cell DNA may occur

Life Cycles
tumor viruses1

Latent Life Cycle

Virus

Cell

Integration (usually)

Transformation

Virus-specific proteins expressed - No mature virus

Changes in the properties of host cell

Tumor Viruses
tumor viruses2
Tumor Viruses

Transformation:

Loss of growth control

Ability to form tumors - viral genes interfere with control of cell replication

DNA may be:

Integrated - replicates with DNA - provirus

Independent - plasmid

tumor viruses3
Tumor Viruses
  • Lecture Outline – We shall see that:
  • Two basic classes of tumor viruses
  • DNA tumor viruses
  • RNA tumor viruses (RETROVIRUSES)
  • These form tumors
  • Virus genome may integrate
  • Virus genes are expressed
  • Viruses often have oncogenes that transform the cell
tumor viruses4
Tumor Viruses
  • Lecture Outline 2
  • Oncogenes are not unique to tumor viruses
  • Cells have homologous genes
  • Proto-oncogenes
  • Transforming virus may carry its own oncogene or activate a cellular proto-oncogene
  • Factors other than viruses can activate a cellular oncogene so that cell is transformed
  • Cellular oncogenes have growth control and differentiation functions
  • Cells also have anti-oncogenes that suppress transformation
slide8

Two Major Classes of Tumor Viruses

DNA Tumor Viruses

DNA viral genome

DNA-dependentDNA polymerase(Host or viral)

Host RNA polymerase

Viral mRNA

Viral protein

slide9

RNA Tumor Viruses

Viral RNA genome

Reverse transcriptase (Virus-encoded)

Viral DNA genome (integrated)

DNA-dependent RNA polymerase (Host RNA pol II)

Viral genomic RNA

Splicing (Host splicing enzymes)

messenger RNA

viral protein

Virus

Important: Use HOSTRNA polymerase to make its genome

An enzyme that normallymakes mRNA

slide10

TRANSFORMATION

Both DNA and RNA tumor viruses can transform cells

Integration occurs (usually)

Similar mechanisms

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

These changes often result from the integration of the viral genome into the host cell DNA

slide11

TRANSFORMATION

  • Among the many altered properties of the TRANSFORMED CELL are:
    • Loss of growth control (loss of contact inhibition in cultured cells)
    • Tumor formation
    • Mobility
    • Reduced adhesion
    • Transformed cells frequently exhibit chromosomal aberrations
dna tumor viruses
DNA Tumor Viruses

DNA genome

mRNA

protein

virus

Host RNA polymerase II

Host enzymes

OR TRANSFORMATIONIn transformation usually only EARLY functions are expressed

dna tumor viruses in human cancer
DNA Tumor Viruses In Human Cancer
  • Papilloma Viruses
  • cause natural cancers in animals
  • cause benign warts
  • ubiquitous
  • epitheliotropic - most human are malignancies of epithelial cells
dna tumor viruses in human cancer1

Papilloma Viruses

  • epidermodysplasia verruciformis
  • wart malignant squamous cell carcinoma
DNA Tumor Viruses In Human Cancer
dna tumor viruses in human cancer2
DNA Tumor Viruses In Human Cancer

Epidermodysplasia

verruciformis

Papilloma virus

dna tumor viruses in human cancer3

Papilloma Viruses

urogenital cancer

wart malignant squamous cell carcinoma

Papilloma viruses are found in 91% of women with cervical cancer

DNA Tumor Viruses In Human Cancer

Squamous cell carcinoma:

Larynx

Esophagus All histologically similar

Lung

10% of human cancers may be HPV-linked

dna tumor viruses in human cancer4

Papilloma Viruses

  • 51 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)
  • German study: 1 in 30 HPV-16 positive women cervical cancer
  • BUT a minority of HPV 16 and 18 positive people get neoplasia
  • Possibility of cofactors (which have been identified in bovine alimentary tract carcinomas)
DNA Tumor Viruses In Human Cancer

EPIDEMIOLOGIAL STUDIES BUT:

HPV 16 and HPV 18 do transform human keratinocytes

dna tumor viruses in human cancer5
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
  • No polyoma virus has been shown to cause transformation in its natural host species
  • PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
  • Polyoma virus transforms cells when the genome is incomplete
  • Viral DNA is linearized and integrated at many sites
dna tumor viruses in human cancer6
DNA Tumor Viruses In Human Cancer

ASSOCIATION OF JC WITH

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

  • 70-80% of the population: JC seropositive
  • Causes progressive multifocal leukoencephalopathy
  • Disease associated with immunosuppression.
  • 1979: the rate of occurrence - 1.5 per 10 million population.
  • Much more common because of AIDS
  • Seen in 5% of AIDS patients
dna tumor viruses in human cancer7

Polyoma Viruses

  • Only tumor antigens are transcribed by host enzyme (RNA pol II)
  • “Early functions”
  • control DNA synthesis in infected cell
  • Early functions Tumor antigens ONCOGENES
DNA Tumor Viruses In Human Cancer
  • Deletions in early functions result in
  • No viral replication
  • No transformation
  • Early functions needed for both lytic infection and transformation
dna tumor viruses in human cancer8
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 cancer9
DNA Tumor Viruses In Human Cancer

SV 40 Oncogenes

Large T antigen

Small T antigenLarge T is found in nucleus and at the cell surface

Polyoma Oncogenes

Large T

Middle T Small T

dna tumor viruses in human cancer10
DNA Tumor Viruses In Human Cancer

In Polyoma Viruses:

T antigens = Oncogenes

T antigens are true viral genes

They are necessary for:

Lytic Infection

Transformation

dna tumor viruses in human cancer11
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 cancer12
DNA Tumor Viruses In Human Cancer
  • Herpes Viruses
  • Considerable evidence for role in human cancer
  • Some very tumorigenic in animals
  • Viral DNA found in small proportion of tumor cells: “hit and run”
  • Epstein-Barr Virus
    • Burkitt’s Lymphoma
    • Nasopharyngeal cancer
    • Infectious mononucleosis
    • Transforms human B-lymphocytes in vitro
dna tumor viruses in human cancer13
DNA Tumor Viruses In Human Cancer

Herpes Viruses continued

  • Human cytomegalovirus
  • Human herpes virus 8 (Kaposi sarcoma-associated virus)
  • Herpes simplex 2 (cervical carcinoma?)

Herpes virus DNA is found in only a small number of herpes-transformed cells

Complex mode of transformation

dna tumor viruses in human cancer14

Hepatitis B Virus

DNA genome

RNA polymerase II

RNA Provirus

Reverse transcriptase

DNA genome

DNA Tumor Viruses In Human Cancer
dna tumor viruses in human cancer hepatitis b continued
DNA Tumor Viruses In Human CancerHepatitis 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 continued1
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

51% of deaths of HB S antigen carriers are from HCC or liver disease

2% of non- HB S positives

dna tumor viruses in human cancer15
DNA Tumor Viruses In Human Cancer

Summary

  • Can transform cells or have lytic life cycle
  • Often integrate into host genome
  • In transformation ONLY early genes are transcribed
dna tumor viruses in human cancer16

= early functions

    • necessary for transformation or lysis
    • No similar gene in host genome
  • T antigen = ONCOGENE

important

important

important

DNA Tumor Viruses In Human Cancer

Summary

T ANTIGENS

rna tumor viruses

virus

virus

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

rna tumor viruses1
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, Some Japanese Islands
  • Human T cell lymphotropic virus -2 (HTLV-2)
  • Hairy cell leukemia
  • HIV?
rna tumor viruses3
RNA Tumor Viruses

A normal retrovirus has:

3 genes

GAG : internal proteins

ENV: Envelope glycoproteins

POL: Enzymes

Reverse transcriptase

Integrase

Protease

rna tumor viruses4
RNA Tumor Viruses
  • RNA is:
  • Diploid Capped and polyadenylated
  • Positive sense (same as mRNA)

Viral RNA cannot be read as mRNA

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 viruses6
RNA Tumor Viruses
  • Groups of Retroviruses
  • Oncovirinae
  • Tumor viruses and similar
  • Lentiviruses
  • Long latent period
  • Progressive chronic disease
  • Visna HIV
  • Spumavirinae

important

important

rna tumor viruses7

Retrovirus Life Cycle

Endocytosis

Fusion of membranes

Release of nucleocapsid to cytoplasm

Nucleus

RNA Tumor Viruses
rna tumor viruses8
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

rna tumor viruses9
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

slide42

Problem of using RNA pol II to copy a gene

RNA synthesis initiation site

promotor

RNA pol II

RNA synthesis termination site

Viral genomicRNA

RT

primer

Reverse transcriptase

dsDNA

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

rna tumor viruses10
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 viruses11

Repeatregion

Repeatregion

DNA

U3 R U5 GAG POL ENV U3 R U5

LTR

RNA Tumor Viruses

Clue: Difference in the two forms

RNA

R U5 GAG POL ENV U3 R

slide45

POLII

RNA termination site

RNA initiation site

R U5

Viral RNA

U3 R

Reverse transcriptase

U3 R U5

U3 R U5

Long terminal repeats are formed

POLII

retroviruses can have only one promotor

POLII

RNA termination site

RNA initiation site

Retroviruses can have only one promotor

LTR

LTR

POLII

Therefore only one long RNA can be made

Therefore mRNA requires processing

Explains why RNA has to be positive sense

U5

slide48

Rous Sarcoma Virus

R U5 GAG POL ENV U3 R

Some retroviruses have an extra gene

“typical retrovirus”

R U5 GAG POL ENV U3 R

SRC

slide49

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 viruses12
RNA Tumor Viruses

Viral Oncogene

V-onc

Cellular Proto-oncogene

C-onc

rna tumor viruses13
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 viruses14
RNA Tumor Viruses
  • Characteristics of Cellular Proto-Oncogenes
  • 1) Normal cellular genes
  • Typical Mendelian inheritance
  • Contain introns (c.f. v-onc)
  • No LTR-like features
  • Always at same place in genome
  • 2) Expressed at some point in many tissues
  • Suggests basic function
  • Growth control - Differentiation - Morphogenesis
  • Highly conserved in evolution
rna tumor viruses15
RNA Tumor Viruses
  • 3) v-onc is most like the c-onc of animal species that is host to the virus
rna tumor viruses16
RNA Tumor Viruses

Acute transforming retroviruses (e.g. RSV) have acquired cellular genes that have an important function in the host cell

The v-onc can cause malignancy in the host cell when part of the virus

Why?

  • V-oncogenes have:
  • Amino acid substitutions
  • Deletions
  • Fusion protein characteristics
  • Enhancer/Promotor LTRs

There may be many v-oncs in a infected cell but only one c-onc

v-oncs are integrated randomly

rna tumor viruses17
RNA Tumor Viruses

The discovery of the acutely transforming retroviruses that contain v-oncs explains how cancers may arise as a result of infection

but

there is no evidence that in nature such viruses cause cancer in humans

These viruses cause rapid cancer in animals in the laboratory

rna tumor viruses18

Avian Leukosis Virus (causes lymphomas)

R U5 GAG POL ENV U3 R

RNA Tumor Viruses

In contrast:

Chronically transforming retroviruses

cause tumors inefficiently after prolonged period of time

No oncogene! – How does it cause a tumor?

rna tumor viruses19
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)

  • Suggest tumor arose from one cell
  • Something must be important about this site for transformation
  • Crucial event must be rare
rna tumor viruses20
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!

rna tumor viruses21

Promotor

Promotor

RNA Tumor Viruses

POL II

POL II

Host DNAU3 R U5 Gag Pol Env U3 R U5 Host DNA

MYC

Initiation of c-myc transcription from a viral promotor inserted UPSTREAM

c-myc mRNA often contains a piece of viral RNA suggesting second LTR is lost

ONCOGENESIS BY PROMOTOR INSERTION

the virus does not have to be inserted upstream

POL II

Enhancer Viral

Enhancer Viral

The virus does not have to be inserted upstream

POL II

Host DNA U3 R U5 Gag Pol Env U3 R U5 Host DNA

MYC

Promotor Host cell

Enhancers may be upstream OR downstream

The viral enhancer may stimulate transcription of the oncogene from the promotor of the oncogene

ONCOGENESIS BY ENHANCER INSERTION

rna tumor viruses22
RNA Tumor Viruses
  • Could C-oncs be involved in NON-VIRAL cancers?
  • C-oncs are a class of genes that could be involved if
  • over expressed
  • mutated
  • There is an abundance of evidence that c-oncs can cause cancers in absence of virus
rna tumor viruses23
RNA Tumor Viruses

Genes can be assigned to sites on specific chromosomes

mosmycabl

mos myc and abl: chromosome 8

fes

fes: chromosome 15

cancers often result from gene translocations
Cancers often result from gene translocations

Translocations near a c-onc may give rise to neoplasia

Disease c-onc translocation

Burkitt’s lymphoma myc 8 to 14

Acute myeloblastic leukemia mos 8 to 21

Chronic myelogenous leukemia abl 9 to 22

(Philadelphia Chromosome))

Acute promyelocytic leukemia fes 15 to 17

Acute lymphocytic leukemia myb 6 deletion *

Ovarian cancer myb 6 to 14*

* break at same site

rna tumor viruses24
RNA Tumor Viruses

Burkitt’s Lymphoma

8:14 translocation

Break in chromosome 14 at q32

myc

Acute myelocytic leukemia7:159:1811:15:17

rna tumor viruses25
RNA Tumor Viruses

Oncogenesis by rearrangement

Tumor c-onc new promotor

Burkitt’s lymphoma myc Ig heavy (8 to 14)

Ig light (8 to 2)

T cell chronic lymphocytic myc T cell receptor (8 to 14)

leukemia

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)

rna tumor viruses26
RNA Tumor Viruses
  • SO: Some cancers may result from a c-onc being under the wrong promotor
  • The promotor may be
  • viral
  • cellular
  • One basis of viral oncogenesis is mutation of the viral oncogene
  • Can cellular oncogenes be mutated to cause cancer?

Yes!

Bladder carcinoma: single point mutation in a cellular oncogene (HaRas)

rna tumor viruses27
RNA Tumor Viruses

What do oncogenes encode?

Proteins that are involved in growth control and differentiation

slide68

Altered growth factor e.g. sis (PDGF)

Altered receptor e.g. erbB (EGF receptor), fms

Cytoplasm

sos

grb2

Altered GTP-binding protein e.g. h-ras/ k-ras

mek

raf-1

P

myc

Altered transcription factors

Map kinase

P

fos/jun

nucleus

oncogenes
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

Always binds

Always binds

Proto-oncogenes

Dominant mutations

Heterozygote

Homozygote

Allele 1 Allele 2 Allele 1 Allele 2

Normal Mutant Mutant Mutant

Binds under special circumstances

Always binds

Always binds

Always binds

Function gained

Function gained

anti oncogenes

Mutation growth

Anti-Oncogenes

Recessive mutations

Rb Gene

Mutant Rb

Mutant Rb

Mutant Rb

Rb

Rb protein

Heterozygote

Homozygote

Function lost

Rb

Binds and controls cell cycle

No binding - Growth continues

anti oncogenes1
Anti-Oncogenes

Retinoblastoma gene has normal regulatory function in many cells

Involved in

Retinoblastoma

Lung carcinomas

Breast carcinomas

anti oncogenes2
Anti-Oncogenes
  • P53
  • Inactivated by
  • deletion
  • point mutation
  • In a series of colorectal cancers all showed:
  • Allele 1: partial or complete deletion
  • Allele 2: Point mutation
dna tumor viruses oncogenes
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 E7
  • All have a sequence in common
  • Mutations in this region abolish transformation capacity
anti oncogenes3
Anti-Oncogenes

Retinoblastoma

Adenovirus E1A

Rb Gene

Rb protein

Rb

Rb

Rb

Cell cycle continues

Stops replication

anti oncogenes4
Anti-Oncogenes

p53

P53 gene

P53 gene

P53 gene

Hepatitis C

P53

Papilloma protease

P53

P53

P53

DNA

Stops replication

replication

replication