ONCOGENIC VIRUS

Dr.T.V.Rao MD

basics

10/7/2012

Dr.T.V.Rao MD

Distinguishing Characteristics of Viruses

Obligate intracellular parasites Extreme genetic simplicity Contain DNA or RNA

Replication involves disassembly and reassembly

Replicate by "one-step growth

10/7/2012

Dr.T.V.Rao MD

Viruses enter the body of the host in a variety of ways, for example...

10/7/2012

Dr.T.V.Rao MD

Routes of entry:
Inhalation ingestion Blood organ t/plant

inoculation

sexual

Congenital / vertical

10/7/2012

Dr.T.V.Rao MD

WHO Estimates
Worldwide, the WHO International Agency for Research on Cancer estimated that in 2002, 20% of human cancers were caused by infection, of which 1015% are caused by one of seven different viruses. The importance of this is that some of these cancers might be easily prevented through vaccination
10/7/2012 Dr.T.V.Rao MD 5

What is Cancer
Cancer results from alterations in critical regulatory genes that control cell proliferation, differentiation, and survival. Studies of tumor viruses revealed that specific genes (called oncogenes) are capable of inducing cell transformation, thereby providing the first insights into the molecular basis of cancer.
10/7/2012 Dr.T.V.Rao MD 6

How virus causes Cancers:

The viral agents causing cancer in eukaryotic animals by integrating in host genome *A virus associated with malignancies in natural host, experimental animals or cell cultures. *viruses which modified proto-oncogene, obligatory host specific, with the ability immortalization, possess genes which stimulate growth and cause cancer.
10/7/2012 Dr.T.V.Rao MD 7

Early History
The theory that cancer could be caused by a virus began with the experiments of Oluf Bang and Vilhelm Ellerman in 1908 who first show that avian erythroblastosis (a form of chicken leukemia) could be transmitted by cellfree extracts. This was subsequently confirmed for solid tumors in chickens in 1910-1911 by Peyton Rous.
10/7/2012 Dr.T.V.Rao MD

Research History
In 1908, Ellerman & Bang first discovered virus, producing leukemia in chicken. In 1911 Peyton Rous 1st shows the presence of filterable sarcoma material that induce the CANCER.

10/7/2012

Dr.T.V.Rao MD

Relationship of viruses with malignancy

Ellerman & Bang (1908) leukemia in fowls Rous (1911) fowl sarcoma Shope isolated Rabbit fibroma virus (1932), papilloma virus (1933) Bittner (1936) Breast Ca in mice
10/7/2012 Dr.T.V.Rao MD 10

Oncovirus
An oncovirus is a virus that can cause cancer. This term originated from studies of acutely-transforming retroviruses in the 195060s, often called oncornaviruses to denote their RNA virus origin. It now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus".
10/7/2012 Dr.T.V.Rao MD

11

by transforming cells cancer

When a virus infects a cell, it expresses proteins that cause the cell to proliferate and/or block apoptosis Cancer is multi-factorial: Oncogenic viruses are very common, only a small % of people infected actually get cancer
Dr.T.V.Rao MD

10/7/2012

12

Major viral cancers

Viruses are involved in about 15% of human cancers:

Cancer of the cervix Cancer of the liver Certain leukemia's & lymphomas Kaposis sarcoma
10/7/2012 Dr.T.V.Rao MD

Copyright John Valentine DMD 1999 13

Classification
Oncovirus

DNA oncogenic viruses

10/7/2012 Dr.T.V.Rao MD

RNA oncogenic viruses

14

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
15

Oncogenic viruses may be RNA or DNA

20% of human cancers believed to be of viral origin These include: Cervical cancer Burkitts lymphoma Hepatocarcinoma Kaposis sarcoma Virus is not only factor
10/7/2012 Dr.T.V.Rao MD 16

Viruses Associated With The Development Of Human Neoplasia

VIRUSES
DNA VIRUSES

NEOPLASMS
Cervical Ca, warts, anogenital carcinoma Cervical carcinoma NPCa, African Burkitts Kaposis sarcoma Hepatocellular Ca Certain B cell lymphomas

Human papilloma virus

Herpes simplex virus II Epstein-Barr virus Human Herpes virus 8 Hepatitis B virus Herpes simplex virus 6 (HBLV)

10/7/2012

Dr.T.V.Rao MD

17

Viruses Associated With The Development Of Human Neoplasia

VIRUSES RNA VIRUSES
Human T-cell leukemia virus I

NEOPLASMS

Some T-cell leukemia, Lymphoma Human T-cell leukemia virus II Some cases of hairy cell leukemia Human immunodeficiency virus Lymphoma; Kaposis sarcoma

10/7/2012

Dr.T.V.Rao MD

18

RNA viruses
Some RNA viruses have also been associated such as the hepatitis virus as well as human T-lymphotropic virus (HTLV-1).
10/7/2012 Dr.T.V.Rao MD 19

Oncogenic viruses
Oncogenesis is the result of genetic changes that alter the expression or function of proteins that play critical roles in the control of cell growth and division Oncogenic viruses cause cancer by inducing changes that affect cell growth and division
10/7/2012 Dr.T.V.Rao MD 20

Oncogenic Retroviruses
More than 40 different highly oncogenic retroviruses have been isolated from a variety of animals, including chickens, turkeys, mice, rats, cats, and monkeys. All of these viruses, like RSV, contain at least one oncogene In some cases, different viruses contain the same oncogenes, but more than two dozen distinct oncogenes have been identified among this group of viruses
10/7/2012 Dr.T.V.Rao MD 21

Changes in cell that are at the roots of cancer

Genetic and epigenetic alterations:
Mutations
Deletions Recombination's Transpositions Epigenetic alterations (DNA methylation, imprinting) Acquisition of viral genetic material
22

Changes in cell that are at the roots of cancer

Genetic and epigenetic alterations:
Mutations
Deletions Recombination's

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.
23

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
24

10/7/2012

Dr.T.V.Rao MD

25

Viruses causing human malignancies

Hepatitis B & C viruses: Hepatocellular Cancer. E-B virus: Nasopharyngeal Ca, Burkitts lymphoma HPV 16 & 18: Ca Cx HTLV: Adult T cell leukemia HHV 8: Kaposis sarcoma
10/7/2012 Dr.T.V.Rao MD 26

10/7/2012

Dr.T.V.Rao MD

27

Retroviruses:
1.Avian leukosis viruses 2.Murine leukosis viruses 3.Murine mammary tumor virus 4.Leukosis-sarcoma viruses 5.Human T cell leukemia virus
10/7/2012 Dr.T.V.Rao MD 28

Retroviridae
Any virus capable of inducing tumors. The RNA tumor viruses (family Retroviridae), which are well defined and rather homogeneous, or the DNA viruses, which contain a number of viruses capable of inducing
10/7/2012 Dr.T.V.Rao MD 29

Cancer
Cancer arises from a combination of dominant gain of function mutations in protooncogenes and recessive loss of function mutations in tumor suppressor genes
10/7/2012

Dr.T.V.Rao MD

30

Understanding Cancer
CANCER
Cancer is an overgrowth of cells bearing cumulative genetic injuries that confer growth advantage over the normal cells [Nowells Law] Cancer cells can be characterized as antisocial, fairly autonomous units that appear to be indifferent to the constraints and regulatory signals imposed on normal cells [Robbins]

10/7/2012

Dr.T.V.Rao MD

31

CANCER CELLS AND NORMAL CELLS

CANCER CELLS
Frequent mitoses Normal cell Nucleus

NORMAL CELLS

Blood vessel

Few mitoses

Abnormal heterogeneous cells

Loss of contact inhibition

Oncogene expression is rare Intermittent or co-ordinated growth factor secretion Presence of tumor suppressor genes
32

Increase in growth factor secretion

Increase in oncogene expression Loss of tumor suppressor genes
10/7/2012 Dr.T.V.Rao MD

CHARACTERISTICS OF CANCER
Clonality
Cancer is a genetic disease at the cellular level. Genetic mutations play a critical role in pathogenesis of cancer. Consequences of genetic instability:
Phenotypic heterogeneity Tumor progression

Proto-oncogenes and oncogenes Dominant and recessive mutations

10/7/2012 Dr.T.V.Rao MD 33

Cancer Genetics
Tumors arise as clones from a single cell. At the cellular level, cancer is a genetic disease. The development of the malignant clone is due to mutations in DNA due to:
Random replication errors Exposure to carcinogens Faulty DNA repair process
10/7/2012 Dr.T.V.Rao MD 34

Cancer Genes
Proto-oncogenes normally promote normal cell
growth; mutations convert them to oncogenes. Tumor suppressor genes normally restrain cell growth; loss of function results in unregulated growth. Mutator or DNA repair genes when faulty, result in an accumulated rate of mutations.

10/7/2012

Dr.T.V.Rao MD

35

ONCOGENE FAMILY

Mouse fibroblast cell line NIH 3T3 can take up foreign D + oncogenes Mouse fibroblast cell line NIH 3T3 can take up foreign DNA, incorporate them into their genome and express them DNA Oncogenes extracted from human tumour cells can transform NIH 3T3 Such transforming genes have been shown to be identical with cellular promote cell proliferation oncogenes 14NA, incorporate them into their genome and express them dominant & highly conserved DNA extracted from human tumour cells can transform NIH 3T3 Such transforming genes have been shown to be identical with cellular types: viral oncogenes [v-oncs] oncogenes 14 cellular oncogenes [c-oncs] Proto-oncogene Mutation Oncogene
10/7/2012 Dr.T.V.Rao MD 36

Viral Carcinogenesis
Viral carcinogens are classified into RNA and DNA viruses. Most RNA oncogenic viruses belong to the family of retroviruses that contain reverse transcriptase mediates transfer of viral RNA into virus specific DNA.
10/7/2012 Dr.T.V.Rao MD 37

Statistical Prevalence in Different Worlds

10/7/2012

Dr.T.V.Rao MD

38

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

10/7/2012

Dr.T.V.Rao MD

39

Two Major Classes of Tumor Viruses

DNA Tumor Viruses
DNA viral genome

DNA-dependent DNA polymerase (Host or viral)

Host RNA polymerase

Viral mRNA

Viral protein
10/7/2012 Dr.T.V.Rao MD 40

RNA Tumor Viruses

Viral RNA genome
Reverse transcriptase (Virus-encoded)

Viral DNA genome (integrated)

(Host

IMPORTANT

DNA-dependent RNA polymerase RNA pol II)

Viral genomic RNA

Splicing (Host splicing enzymes)

messenger RNA viral protein Virus

10/7/2012 Dr.T.V.Rao MD

Important: Use HOST RNA polymerase to make its genome An enzyme that normally makes mRNA
41

Small DNA tumor viruses

Adenovirus Human virus but only causes cancer in nonhuman cells

SV40
Mesothelioma

HPV
Cervical Cancer Squamous cell anal carcinoma Penile cancer Oral cancers

42

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

43

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

Burkitts Lymphoma
Nasopharyngeal cancer Infectious mononucleosis Transforms human B-lymphocytes in vitro
10/7/2012 Dr.T.V.Rao MD 44

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
10/7/2012 Dr.T.V.Rao MD 45

DNA Tumor Viruses In Human Cancer

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)
10/7/2012 Dr.T.V.Rao MD 46

Human Papillomavirus (HPV)

Human Papillomavirus (HPV) is a doublestranded DNA virus of the family Papovaviridae. It infects only epithelial cells in humans such as skin and mucus membranes. It can affect the lower genital tract including the vulva, vagina, urethra, penis, anal canal and perianal skin
10/7/2012 Dr.T.V.Rao MD 47

DNA viruses Human Papilloma virus

(HPV), a DNA virus, causes transformation in

10/7/2012

cells through interfering with tumor suppressor proteins such as p53. Interfering with the action of p53 allows a cell infected with the virus to move into a different stage of the cell cycle, enabling the virus genome to be replicated. Forcing the cell into the S phase of the cell cycle could cause the cell to become transformed types of HPV increase the risk of, e.g., cervical cancer.
Dr.T.V.Rao MD

48

10/7/2012

Dr.T.V.Rao MD

49

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 lymphoblastic malignancies
50

Epstein-Barr virus (Human herpes virus 4)

EBV is the herpes virus that is most strongly associated with cancer. It infects primarily lymphocytes and epithelial cells. In lymphocytes, the infection is usually nonproductive, while virus is shed (productive infection) from infected epithelial cells.
10/7/2012 Dr.T.V.Rao MD 51

Burkitt's lymphoma
Burkitt's lymphoma in the tropics, where it is more common in malaria-endemic regions Nasopharyngeal cancer, particularly in China and SE Asia, where certain diets may act as co-carcinogens B cell lymphomas in immune suppressed individuals (such as in organ transplantation or HIV) Hodgkin's lymphoma in which it has been detected in a high percentage of cases (about 40% of affected patients) X-linked lymphoproliferative Disease (Duncan's syndrome)
10/7/2012 Dr.T.V.Rao MD 52

Infectious mononucleosis
EBV also causes infectious mononucleosis, otherwise known as glandular fever. This is a self-resolving infection of B-lymphocytes which proliferate benignly. Often infection goes unnoticed (it is sub-clinical) and about half of the population in western countries has been infected by the time they reach 20 years of age. Why this virus causes a benign disease in some populations but malignant disease in others is unknown
10/7/2012 Dr.T.V.Rao MD 53

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
54

Human Herpes Virus 8 (HHV-8, Kaposi's Sarcoma Herpes Virus)

HHV-8 infects lymphocytes and epithelial/endothelial cells and is the causative agent of Kaposi's sarcoma. It has also been associated with hematologic malignancies, including primary effusion lymphoma, Multicentric Castleman's (also Castelman's) disease (MCD), MCD-related immunoblastic/plasmablastic lymphoma and various atypical lymphoproliferative disorders
10/7/2012 Dr.T.V.Rao MD 55

Kaposi's sarcoma-associated herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is associated with Kaposis sarcoma, a type of skin cancer. Epstein-Barr virus (EBV or HHV-4) is associated with four types of cancers Merkel cell polyomavirus a polyoma virus is associated with the development of Merkel cell cancer
10/7/2012 Dr.T.V.Rao MD 56

RNA oncogenic viruses

Retroviridae
Human T cell leukemia viruses
(HTLV-1 and HTLV-2)
Causes Adult T cell leukemia Lymphoma

Feline leukemia virus (FeLV)

Contagious Causes leukemia and lymphoma in cats

Related to presence of reverse transcriptase Some contain promoters that turn on other oncogenes 10/7/2012 Dr.T.V.Rao MD

57

RNA Tumor Viruses

Groups of Retroviruses
Oncovirinae
Lentiviruses
important

Tumor viruses and similar

important

Long latent period Progressive chronic disease Visna HIV

58

Spumavirinae

VIRAL AGENTS: DNA viruses

Human Papillomavirus [HPV types 16, 18, 31, 33 & 35]

Interruption of the E1/E2 ORF E2 is not expressed

10/7/2012

Over-expression MD E6 & E7 Dr.T.V.Rao of

59

VIRAL AGENTS: DNA viruses

Epstein-Barr Virus [EBV]

in Burkitts, B-cell & Hodgkins lymphomas + NP ca tropism: CD21+ cells [e.g., B cells, epithelial cells] mechanism: viral entry episomal existence latency (+) LMP-1, EBNA-1, EBNA-2 immortalization

Hepatitis B virus [HBV]

induction of chronic hepatocyte injury (+) HBx HBx activates protein kinase c for transformation
Dr.T.V.Rao MD 60

10/7/2012

Hepatitis B
DNA virus with RNA intermediate In tumors virus is integrated with little gene expression Believed to be from chronic liver damage/loss and replacement causing increased mutations (similar to SOS response?)
10/7/2012 Dr.T.V.Rao MD 61

DNA Tumor Viruses In Human Cancer

Hepatitis B Virus
DNA genome
RNA polymerase II Host enzyme

RNA Provirus
Reverse transcriptase

DNA genome

Viral enzyme

62

HEPADNAVIRIDAE HEPATITIS B VIRUS

Hepatitis B virus is very different from the other DNA tumor viruses. Indeed, even though it is a DNA virus, it is much more similar to the oncornaviruses (RNA tumor viruses) in its mode of replication. The DNA is transcribed into RNA not only for the manufacture of viral proteins but for genome replication. Genomic RNA is transcribed back into genomic DNA. This is called reverse transcription. The latter is not typical of most DNA tumor viruses but reverse transcription is a very important factor in the life cycles of RNAtumor viruses
10/7/2012 Dr.T.V.Rao MD 63

HCC is one of the most common tumors worldwide

10/7/2012

Dr.T.V.Rao MD

64

Hepatocellular carcinoma
Hepatocellular carcinoma (HCC, also called malignant hepatoma) is a primary malignancy (cancer) of the liver. Most cases of HCC are secondary to either a viral hepatitide infection (hepatitis B or C) or cirrhosis (alcoholism being the most common cause of hepatic cirrhosis).In countries where hepatitis is not endemic, most malignant cancers in the liver are not primary HCC but metastasis (spread) of cancer from elsewhere in the body, e.g., the colon.
10/7/2012 Dr.T.V.Rao MD 65

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

10/7/2012

Dr.T.V.Rao ? HIVMD

66

Proto-oncogenes
Heterozygote

Dominant mutations
Allele 2 Mutant

Homozygote

Allele 1 Normal

Allele 1 Mutant

Allele 2 Mutant

Binds under special circumstances

Mutant always binds

Always binds

Mutant always binds

Mutant always binds

Always binds

10/7/2012 Function

gained

Dr.T.V.Rao MD

Function gained

67

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

Rb

Rb protein
Heterozygote Homozygote

Rb

Function lost

Binds and controls cell cycle

10/7/2012

No binding - Growth continues

Dr.T.V.Rao MD 68

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

Retinoblastoma
Lung carcinomas Breast carcinomas
69

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

70

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

Retinoblastoma
Lung carcinomas Breast carcinomas
10/7/2012 Dr.T.V.Rao MD 71

Anti-Oncogenes
Retinoblastoma Rb Gene Adenovirus E1A

Rb protein

Rb

105kD

Rb

Rb

Stops 10/7/2012replication

Dr.T.V.Rao MD

Cell cycle continues

72

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
73

Anti-Oncogenes
p53
P53 gene P53 gene Hepatitis C P53 gene Papilloma

P53

P53

P53

Papilloma proteolysis P53 DNA replication Dr.T.V.Rao MD replication

Stops replication 10/7/2012

74

For more articles of Interest on Infectious Diseases visit me.

10/7/2012

Dr.T.V.Rao MD

75

 Programme Created by Dr.T.V.Rao MD for Medical and Health care Professionals in the Developing World
Email

doctortvrao@gmail.com
10/7/2012 Dr.T.V.Rao MD 76