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    Tumour Viruses

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    Charles Townsend
    Viruses can cause cancer through several mechanisms. Some viruses integrate into the host cell genome and express viral oncogenes that drive cell proliferation and prevent apoptosis. This allows the cell to accumulate additional genetic changes and become cancerous. Viruses like HPV and EBV also express genes during latent infections that promote cell survival and division. However, viral infection alone is usually not enough to cause cancer without additional genetic alterations in the host cell or a compromised immune system.

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    Tumour Viruses

    Uploaded by

    Charles Townsend
    747 views57 pages
    Viruses can cause cancer through several mechanisms. Some viruses integrate into the host cell genome and express viral oncogenes that drive cell proliferation and prevent apoptosis. This allows the cell to accumulate additional genetic changes and become cancerous. Viruses like HPV and EBV also express genes during latent infections that promote cell survival and division. However, viral infection alone is usually not enough to cause cancer without additional genetic alterations in the host cell or a compromised immune system.

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    oncogenic viruses

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    Viruses can cause cancer through several mechanisms. Some viruses integrate into the host cell genome and express viral oncogenes that drive cell proliferation and prevent apoptosis. This allows the cell to accumulate additional genetic changes and become cancerous. Viruses like HPV and EBV also express genes during latent infections that promote cell survival and division. However, viral infection alone is usually not enough to cause cancer without additional genetic alterations in the host cell or a compromised immune system.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    747 views57 pages

    Tumour Viruses

    Uploaded by

    Charles Townsend
    Viruses can cause cancer through several mechanisms. Some viruses integrate into the host cell genome and express viral oncogenes that drive cell proliferation and prevent apoptosis. This allows the cell to accumulate additional genetic changes and become cancerous. Viruses like HPV and EBV also express genes during latent infections that promote cell survival and division. However, viral infection alone is usually not enough to cause cancer without additional genetic alterations in the host cell or a compromised immune system.

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    Viruses cause cancer

    Download lecture at: flemingtonlab.com

    Viruses cause cancer


    Why has the study of viruses and cancer been important?

    Viruses cause cancer


    Why has the study of viruses and cancer been important? - We learn about the basic mechanisms of specific types
    of tumors.

    Viruses cause cancer


    Why has the study of viruses and cancer been important? - We learn about the basic mechanisms of specific types
    of tumors.

    - We identify fundamental pathways important for oncogenesis


    - viruses are lower complexity

    - We can identify potential unique therapeutic targets for viral associated tumors

    Viruses cause cancer


    30-40% of cancers are known to have viral etiology -But as more research is done, this percentage is likely to be found to be higher

    Major human Oncogenic Viruses


    DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposis Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C
    6

    Changes in cell that are at the roots of cancer

    Changes in cell that are at the roots of cancer


    Genetic and epigenetic alterations:

    Changes in cell that are at the roots of cancer


    Genetic and epigenetic alterations:
    Mutations
    Deletions Recombinations

    Transpositions
    Epigenetic alterations (DNA methylation, imprinting) Acquisition of viral genetic material

    Changes in cell that are at the roots of cancer


    Genetic and epigenetic alterations:
    Mutations
    Deletions Recombinations

    Transpositions
    Epigenetic alterations (DNA methylation, imprinting) Acquisition of viral genetic material

    Various combinations of these lead to the development of cancers - some


    viruses contribute single hits while others contribute multiple hits.
    10

    Source of genetic alterations


    Inherited

    Somatic
    - Random - Transposition - Exposure to deleterious environmental agents
    - Radiation - carcinogenic chemicals

    - Viruses
    - Other persistent infections
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    How do Viruses contribute to cancer?


    Integrations that cause activation or inactivation of oncogenes or tumor suppressors (e.g. RNA viruses)

    Expression of genes that alter key signal transduction pathways - this is our focus
    Chronic activation of inflammatory responses

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    Why do viruses cause cancer?

    13

    Why do viruses cause cancer?


    Viruses and cancer cells have similar needs
    Proliferation control Cell death control Modulation of immune response Induction of vascularization Metastasis (tumor)/cell migration (viruses)

    14

    If youre infected, does this mean that you will get cancer?

    15

    If youre infected, does this mean that you will get cancer?
    No
    Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs

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    If youre infected, does this mean that you will get cancer?
    No
    Viruses did not specifically evolve with the need to cause cancer - they simply have similar (but distinct) needs

    Development of tumors almost always requires:


    Additional genetic alterations and/or Compromised host (e.g. immuno-suppression)

    17

    Major human Oncogenic Viruses


    DNA Viruses Small DNA tumor viruses - Adenovirus - SV40 - Human Papilloma virus (HPV) Herpesviruses (large) - Epstein Barr virus (EBV) - Kaposis Sarcoma Herpesvirus (KSHV) Other - Hepatitis virus B RNA viruses Human T-cell Leukemia Virus 1 (HTLV1) Hepatitis virus C
    18

    Small DNA tumor viruses


    Adenovirus
    Human virus but only causes cancer in non-human cells

    SV40
    Mesothelioma

    HPV
    Cervical Cancer Squamous cell anal carcinoma Penile cancer Oral cancers
    19

    Small DNA tumor viruses


    HPV SV40 Adenovirus
    Normally replicate episomally but almost always found integrated in associated tumors - why?

    20

    Small DNA tumor viruses


    HPV SV40 Adenovirus
    Normally replicate episomally but almost always found integrated in associated tumors - why?

    Replication must be abortive


    HPV, viral encoded negative regulatory factor must be deleted

    21

    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

    10% of human cancers may be HPV-linked 16% of all female cancers linked to HPV

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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)

    Effective Vaccine (quadrivalent recombinant HPV 6, 11, 16 and 18 proteins made in yeast - Gardasil) 23

    Papilloma Viruses
    The important transforming genes in papilloma viruses are the non-structural regulatory genes, E6 and E7 HPV is normally episomal but is always integrated in tumors

    24

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    Adenoviruses
    Highly oncogenic in animals Only part of virus integrated Always the same part Early (regulatory) genes E1A and E1B = Oncogenes
    26

    SV40
    The important transforming gene is T Ag - provides similar functions as E1A +
    E1B (Adenovirus) and E6 and E7 (HPV)

    27

    Abortive replication is key to oncogenesis by these small viruses


    Expression of early (regulatory) genes in absence of structural genes and virus production
    Can occur by infection of non-permissive host Can occur by integrations that delete regions of viral genome required for replication but leave early genes intact.

    28

    Small DNA Tumor Viruses


    What are the needs of small DNA tumor viruses that make them oncogenic and What are the key mechanisms through which they attain their needs?

    29

    Small DNA Tumor Viruses


    DNA viral genome
    Utilizes Host Cell DNA Replication Machinery Host RNA polymerase

    Need cells that are in Sphase to replicate viral genome

    Viral mRNA
    Host enzymes

    Viral protein
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    Inappropriate activation of cell cycle

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    Inappropriate activation of cell cycle


    Apoptosis

    34

    Inappropriate activation of cell cycle


    Apoptosis
    e.g. -Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis

    - Defense mechanism against rogue proliferating cells?

    35

    Inappropriate activation of cell cycle


    Apoptosis
    e.g. - Overexpression of E2F1 or c-Myc induces cell cycle and apoptosis - Same is true for over-expression of Adenovirus E1A or HPV E7

    36

    Encode early genes that inhibit apoptosis


    Adenovirus E1B
    HPV E6 SV40 T Ag

    37

    SV40 and HPV

    38

    Adenovirus
    E1B is Bcl2 family member - blocks function of proapoptotic Bcl2 family members through dimerization

    39

    Summary
    Small DNA tumor viruses usually replicate in episomal form but are found integrated in viral associated tumors

    Early genes promote cell cycle progression and prevent apoptosis


    Adenovirus - E1A (cell cycle) and E1B (apoptosis)

    HPV - E7 (cell cycle) and E6 (apoptosis)


    SV40 - T Ag (cell cycle and apoptosis)
    40

    Herpes viruses
    Oncogenic members:
    Epstein Barr virus (EBV)
    Kaposis Sarcoma Herpes virus (KSHV) Oncogenic mechanisms are distinct from small DNA tumor viruses

    - Dont need to integrate


    - Cell cycle is not driven by lytic replication regulatory genes
    41

    Herpes viruses
    Hallmark of herpesviruses:

    42

    Herpes viruses
    Hallmark of herpesviruses:
    Existence of latent stage (in addition to lytic/replicative stage)

    43

    Herpes viruses
    Lytic replication phase for herpesviruses:

    44

    Herpes viruses
    Lytic replication phase for herpesviruses:
    - Herpesviruses are large and encode 80-100 lytic associated genes

    - Encode their own DNA polymerase and replication


    accessory enzymes - Therefore, they dont require an S-phase environment for replication - Encode early genes that induce cell cycle arrest
    45

    Herpes viruses
    Latency:
    - Small subset of viral genes are expressed that are not expressed during lytic replication.

    - Latency is partly a way for virus to hide from immune system


    - In cases of EBV and KSHV, latency genes can also induce cell differentiation/activation programs that facilitate expansion of infected cell population and induce trafficking to specific lymphoid compartments that are suited to the life cycle of the virus
    46

    Herpes viruses
    Human Herpesviruses and latency function:
    Epstein Barr virus (EBV) - multiple functions Kaposis Sarcoma Herpes virus (KSHV) - multiple functions Cytomegalovirus (CMV) - Stealth mechanism Herpes Simplex (HSV) - Stealth mechanism

    47

    Epstein Barr virus


    Pathologies in immuno-competent individuals Infectious mononucleosis Burkitts Lymphoma Hodgkins lymphoma Nasopharyngeal carcinoma Pathologies in immuno-compromised individuals Post-transplant lymphoproliferative diseases (PTLD) Hodgkins lymphoma A variety of non-Hodgkins lymphoblastoid malignancies

    48

    Epstein Barr virus


    Latency genes
    Non-antigenic - EBNA1 (Epstein Barr Nuclear Antigen 1) episomal replication and segregation function

    Antigenic - EBNA2 - EBNA3A, 3B, 3C - EBNA-LP - LMP1 (Latent Membrane Protein 1) - LMP2A
    Those in Red are key regulatory genes involved in B cell activation
    49

    50

    Epstein Barr virus


    4 different types of latency
    True Latency - no viral gene expression EBNA1 only - EBNA1 (non-antigenic) Default - EBNA1, LMP1, and LMP2 (moderately antigenic) Growth - EBNA1, LMP1, LMP2, EBNA2, EBNALP, EBNA3A, 3B, 3C (highly antigenic)

    Growth program -Initial infection (prior to immune response) - Immuno-compromised individuals - in vitro infection of nave peripheral blood lymhocytes

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    Epstein Barr virus


    Greater than 90% of US population are carriers of EBV

    -Only small percentage of carriers develop tumors - who?


    - Immuno-compromised - allows full set of oncongenic
    genes to be expressed
    - Immuno-competent who have multiple additional genetic hits

    EBV does not integrate - exists as an extrachromosomal episome


    54

    Kaposis Sarcoma Herpes Virus - HHV-8


    Kaposis 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
    55

    Hepatitis B and C
    Long latency period to development of HCC (Hepatocellular Carcinoma) 20-30 years Mechanism is probably due to chronic inflammatory response

    56

    Silver lining to viral associate cancers


    Offer unique targets not common to normal uninfected cells
    Examples:
    HPV - Gardasil EBV - In vitro production of EBV specific CTLs for PTLD - Treatment with agents that induce lytic cycle (butyrate plus Gancyclovir) KSHV - Anti-retroviral therapy

    57

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