Oncogenic virus

04/11/2023 Dr.T.V.Rao MD 1

ONCOGENIC VIRUS basics

Dr.T.V.Rao MD

04/11/2023 Dr.T.V.Rao MD 2

Distinguishing Characteristics of Viruses

Obligate intracellular parasites

Extreme genetic simplicity

Contain DNA or RNA

Replication involves disassembly and reassembly

Replicate by "one-step growth”

04/11/2023 Dr.T.V.Rao MD 3

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

04/11/2023 Dr.T.V.Rao MD 4

Routes of entry:

sexual

Inhalation

inoculation

Bloodorgan t/plant

ingestion

Congenital / vertical

04/11/2023 Dr.T.V.Rao MD 5

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 10–15% are caused by one of seven different viruses. The importance of this is that some of these cancers might be easily prevented through vaccination

04/11/2023 Dr.T.V.Rao MD 6

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.

04/11/2023 Dr.T.V.Rao MD 7

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.

04/11/2023 Dr.T.V.Rao MD 8

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 cell-free extracts. This was subsequently confirmed for solid tumors in chickens in 1910-1911 by Peyton Rous.

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.

04/11/2023 Dr.T.V.Rao MD 9

04/11/2023 Dr.T.V.Rao MD 10

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

04/11/2023 Dr.T.V.Rao MD 11

Oncovirus• An oncovirus is a virus that can cause

cancer. This term originated from studies of acutely-transforming retroviruses in the 1950–60s, 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".

04/11/2023 Dr.T.V.Rao MD 12

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

04/11/2023 Dr.T.V.Rao MD 13

Major viral cancers

Copyright John Valentine DMD 1999

–Cancer of the cervix–Cancer of the liver–Certain leukemia's & lymphomas

–Kaposi’s sarcoma

Viruses are involved in about 15% of human cancers:

Classification

Oncovirus

DNA oncogenic viruses

RNA oncogenic viruses

04/11/2023 Dr.T.V.Rao MD 14

15

Major human Oncogenic VirusesMajor human Oncogenic VirusesDNA Viruses

Small DNA tumor viruses- Adenovirus- SV40- Human Papilloma virus (HPV)

Herpesviruses (large)- Epstein Barr virus (EBV)- Kaposi’s Sarcoma Herpesvirus (KSHV)

Other- Hepatitis virus B

RNA virusesHuman T-cell Leukemia Virus 1 (HTLV1)Hepatitis virus C

Oncogenic viruses may be RNA or DNA

• 20% of human cancers believed to be of viral origin

• These include:– Cervical cancer– Burkitt’s lymphoma– Hepatocarcinoma– Kaposi’s sarcoma

• Virus is not only factor16Dr.T.V.Rao MD04/11/2023

04/11/2023 Dr.T.V.Rao MD 17

Viruses Associated With The Development Of Human Neoplasia

VIRUSES NEOPLASMSDNA VIRUSESHuman papilloma virus Cervical Ca, warts, ano-

genital carcinomaHerpes simplex virus II Cervical carcinomaEpstein-Barr virus NPCa, African Burkitt’sHuman Herpes virus 8 Kaposi’s sarcomaHepatitis B virus Hepatocellular CaHerpes simplex virus 6 Certain B cell (HBLV) lymphomas

04/11/2023 Dr.T.V.Rao MD 18

VIRUSES NEOPLASMSRNA VIRUSESHuman T-cell leukemia virus I Some T-cell leukemia, Lymphoma Human T-cell leukemia virus II Some cases of hairy cell leukemia Human immunodeficiency virus Lymphoma; Kaposi’s Promote sarcoma

Viruses Associated With The Development Of Human Neoplasia

04/11/2023 Dr.T.V.Rao MD 19

RNA viruses

• Some RNA viruses have also been associated such as the hepatitis virus as well as human T-lymphotropic

• virus (HTLV-1).

04/11/2023 Dr.T.V.Rao MD 20

• 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

04/11/2023 Dr.T.V.Rao MD 21

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

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

23



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.

24

• 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

How do Viruses contribute to cancer?

How do Viruses contribute to cancer?

04/11/2023 Dr.T.V.Rao MD 25

04/11/2023 Dr.T.V.Rao MD 26

Viruses causing human malignancies

• Hepatitis B & C viruses: Hepatocellular Cancer.

• E-B virus: Nasopharyngeal Ca, Burkitt’s lymphoma

• HPV 16 & 18: Ca Cx• HTLV: Adulât T cell leukemia• HHV 8: Kaposi’s sarcoma

04/11/2023 Dr.T.V.Rao MD 27

04/11/2023 Dr.T.V.Rao MD 28

Retroviruses:• 1.Avian leukosis viruses• 2.Murine leukosis

viruses• 3.Murine mammary

tumor virus• 4.Leukosis-sarcoma

viruses• 5.Human T cell

leukemia virus

04/11/2023 Dr.T.V.Rao MD 29

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

04/11/2023 Dr.T.V.Rao MD 30

Cancer• Cancer arises from

a combination of dominant gain of function mutations in proto- oncogenes and recessive loss of function mutations in tumor suppressor genes

04/11/2023 Dr.T.V.Rao MD 31

Understanding Cancer

CANCER

Cancer is an overgrowth of cells bearing cumulative genetic injuries that confer growth advantage over the normal cells [Nowell’s 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 [Robbin’s]

04/11/2023 Dr.T.V.Rao MD 32

CANCER CELLS AND NORMAL CELLS CANCER CELLS AND NORMAL CELLS CANCER CELLS NORMAL CELLS

Loss of contact inhibition

Increase in growth factor secretion

Increase in oncogene expression

Loss of tumor suppressor genes

Oncogene expression is rare

Intermittent or co-ordinatedgrowth factor secretion

Presence of tumor suppressorgenes

Normalcell

Fewmitoses

Frequentmitoses

Nucleus

Blood vessel

Abnormalheterogeneous cells

04/11/2023 Dr.T.V.Rao MD 33

CHARACTERISTICS OF CANCERClonality

• 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

04/11/2023 Dr.T.V.Rao MD 34

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

04/11/2023 Dr.T.V.Rao MD 35

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.

04/11/2023 Dr.T.V.Rao MD 36

ONCOGENE FAMILY

+ oncogenes

Oncogenes

promote cell proliferation

dominant & highly conserved

types: viral oncogenes [v-oncs]

cellular oncogenes [c-oncs]

Proto-oncogene “Mutation” Oncogene

Mouse fibroblast cell line NIH 3T3 can take up foreign DMouse fibroblast cell line NIH 3T3 can take up foreign DNA, incorporate them into their genome and express them•DNA extracted from human tumour cells can transform NIH 3T3•Such transforming genes have been shown to be identical with cellular oncogenes14NA, incorporate them into their genome and express them•DNA extracted from human tumour cells can transform NIH 3T3•Such transforming genes have been shown to be identical with cellular oncogenes14

04/11/2023 Dr.T.V.Rao MD 37

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.

04/11/2023 Dr.T.V.Rao MD 38

Statistical Prevalence in Different Worlds

04/11/2023 Dr.T.V.Rao MD 39

DNA Tumor Viruses In Human CancerDNA Tumor Viruses In Human Cancer

AdenovirusesHighly 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

04/11/2023 Dr.T.V.Rao MD 40

Two Major Classes of Tumor Viruses

DNA Tumor VirusesDNA viral genome

Host RNA polymerase

Viral mRNA

Viral protein

DNA-dependentDNA polymerase(Host or viral)

04/11/2023 Dr.T.V.Rao MD 41

RNA Tumor VirusesViral 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

IMPORTANT

42

• Adenovirus• Human virus but only causes cancer in non-

human cells• SV40• Mesothelioma

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

Small DNA tumor virusesSmall DNA tumor viruses

43

DNA Tumor Viruses In Human Cancer

Papilloma Viruses

urogenital cancer

wart malignant squamous cell carcinomaPapilloma viruses are found in 91% of women with cervical cancer

Squamous cell carcinoma:LarynxEsophagus All histologically similarLung

10% of human cancers may be HPV-linked

04/11/2023 Dr.T.V.Rao MD 44


Herpes VirusesConsiderable 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

04/11/2023 Dr.T.V.Rao MD 45

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

04/11/2023 Dr.T.V.Rao MD 46

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)

04/11/2023 Dr.T.V.Rao MD 47

Human Papillomavirus (HPV) • Human Papillomavirus

(HPV) is a double-stranded 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

04/11/2023 Dr.T.V.Rao MD 48

DNA virusesHuman Papilloma virus

• (HPV), a DNA virus, causes transformation in 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.

04/11/2023 Dr.T.V.Rao MD 49

50

Epstein Barr virusEpstein Barr virusPathologies in immuno-competent individuals

• Infectious mononucleosis

• Burkitt’s Lymphoma

• Hodgkin’s lymphoma

• Nasopharyngeal carcinoma

Pathologies in immuno-compromised individuals

• Post-transplant lymphoproliferative diseases (PTLD)• Hodgkin’s lymphoma• A variety of non-Hodgkin’s lymphoblastic malignancies

04/11/2023 Dr.T.V.Rao MD 51

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 non-productive, while virus is shed (productive infection) from infected epithelial cells.

04/11/2023 Dr.T.V.Rao MD 52

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)

04/11/2023 Dr.T.V.Rao MD 53

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

54

Kaposi’s Sarcoma Herpes Virus - HHV-8

Kaposi’s Sarcoma Herpes Virus - HHV-8

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

04/11/2023 Dr.T.V.Rao MD 55

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

04/11/2023 Dr.T.V.Rao MD 56

Kaposi's sarcoma-associated herpesvirus

• Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) is associated with Kaposi’s 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

04/11/2023 Dr.T.V.Rao MD 57

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

58

RNA Tumor VirusesRNA Tumor VirusesGroups of Retroviruses• Oncovirinae

Tumor viruses and similar

• Lentiviruses

Long latent period

Progressive chronic disease

Visna HIV

• Spumavirinae

important

important

04/11/2023 Dr.T.V.Rao MD 59

VIRAL AGENTS: DNA viruses

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

Interruption of the E1/E2 ORF

E2 is not expressed

Over-expression of E6 & E7

04/11/2023 Dr.T.V.Rao MD 60

VIRAL AGENTS: DNA viruses

Epstein-Barr Virus [EBV]

in Burkitt’s, B-cell & Hodgkin’s 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

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?)

61Dr.T.V.Rao MD04/11/2023

62


Hepatitis B VirusDNA genome

RNA polymerase II

RNA Provirus

Reverse transcriptase

DNA genome

Host enzyme

Viral enzyme

04/11/2023 Dr.T.V.Rao MD 63

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 RNA-tumor viruses

04/11/2023 Dr.T.V.Rao MD 64

HCC is one of the most common tumors worldwide

04/11/2023 Dr.T.V.Rao MD 65

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.

04/11/2023 Dr.T.V.Rao MD 66

RNA Tumor VirusesRNA Tumor Viruses

• Human T cell lymphotropic virus -2 (HTLV-2)

Hairy cell leukemia

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

• HIV?

04/11/2023 Dr.T.V.Rao MD 67

Proto-oncogenesProto-oncogenesHeterozygote 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

04/11/2023 Dr.T.V.Rao MD 68

Anti-OncogenesAnti-Oncogenes

Rb Gene Mutant Rb Mutant Rb

Rb

Rb

Rb protein

Binds and controls cell cycle No binding - Growth continues

Mutant Rb

Recessive mutations

Function lost

Mutation growth

Heterozygote Homozygote

69

Anti-OncogenesAnti-OncogenesRetinoblastoma gene has normal regulatory function in many cells

Involved in

Retinoblastoma

Lung carcinomas

Breast carcinomas

70

RNA Tumor VirusesRNA Tumor Viruses

What do oncogenes encode?Proteins that are involved in growth control and differentiation

Growth factorsGrowth factor receptorsSignal transduction proteinsTranscription factors

04/11/2023 Dr.T.V.Rao MD 71

Anti-OncogenesAnti-OncogenesRetinoblastoma gene has normal regulatory function in many cells

Involved in

Retinoblastoma

Lung carcinomas

Breast carcinomas

04/11/2023 Dr.T.V.Rao MD 72

Anti-OncogenesAnti-OncogenesRb Gene

RbRb protein

Rb

Stops replication

Rb

Adenovirus E1A

Cell cycle continues

Retinoblastoma

105kD

73

Anti-OncogenesAnti-OncogenesP53Inactivated by

• deletion

• point mutation

In a series of colorectal cancers all showed:

• Allele 1: partial or complete deletion

• Allele 2: Point mutation

04/11/2023 Dr.T.V.Rao MD 74

Anti-OncogenesAnti-Oncogenesp53

P53 gene P53 gene P53 gene

P53

P53 DNA

Stops replication

Hepatitis C

P53

replication replication

Papilloma proteolysis

P53

Papilloma

04/11/2023 Dr.T.V.Rao MD 75

For more articles of Interest on Infectious Diseases visit me….

04/11/2023 Dr.T.V.Rao MD 76

• Programme Created by Dr.T.V.Rao MD for Medical and

Health care Professionals in the Developing World

• Email• [email protected]

Health & Medicine

Oncogenic virus