Oncogenic Viruses by Dr. Rakesh Prasad Sah

1. By Dr. Rakesh Prasad Sah
Assistant Professor, Microbiology
Oncogenic Viruses

2. Introduction
• Viruses that produce tumors in hosts/experimental animals
or
induce malignant transformation of cells in culture are called Oncogenic
viruses.

3. Features of Viral Oncogenesis
• Causes cancer in humans & animals
• long latency between viral infection and tumorigenesis
• modulate growth control pathways in cells
• viral markers are present in tumor cells

4. Genes Regulating Host Cell Growth
• Four categories of genes present in host which regulate the cellular growth and
proliferation.
• Defect in any of these regulatory genes  lead to transformation of the normal
cells  abnormal tumor cells.
• Proto-oncogenes
– Promote host cells growth & proliferation
– Essential for life
– Over activation of protooncogene  transformation of host cells

5. • Anti-oncogenes or tumor suppressor genes
– Continuously check cellular growth and proliferation and supress any abnormal
proliferation of cells.
– Inactivation of tumor suppressor genes permits the abnormal event to occur
resulting in cell transformation.
• DNA repair genes:
– Normal host genes that repair any mutations occurring during the cell growth.
– Failure of DNA repair genes lead to inability to repair the damaged DNA and may
lead to persistent mutation.
Genes Regulating Host Cell Growth

6. • Apoptosis-regulatory genes:
– Control the programmed cell death
– Either up-regulate or down-regulate apoptosis depending on the
requirement.
– May act as proto-oncogenes or tumor suppressor genes.
– Mutations in apoptosis-regulatory genes are another mechanism
by which the cellular transformation is accelerated.
Genes Regulating Host Cell Growth

8. • Oncogenesis -An abnormal growth of tissue resulting from uncontrolled, progressive
multiplication of cells and serving no physiological function. Result of genetic changes that
alter the expression or function of proteins that play critical roles in the control of cell
growth and division.
• Proto-oncogenes - normal (pre-mutation) (pre-diseased) genes
– present in normal cells
– conserved in their genomes
– code for proteins which regulate cell growth & differentiation
• Oncogenes
– mutated versions of proto-oncogenes
– contribute to cancer development by disrupting a cell's ability to control its own growth.

9. C-onc (Cellular Oncogenes)
• Cellular counter part of viral
oncogenes present in cancer cells
• Encodes proteins triggering
transformation of normal cells
V-onc (Viral Oncogenes)
•Present in viruses
•Essential for replication of virus.
•Also called ‘cancer genes’
•Encodes proteins triggering
transformation of normal
cells into cancer cells

11. TRANSFORMATION
• alteration in a cell’s properties that leads to immortalization and different growth patterns that
result from alteration in cell cycle.
• Acute transforming viruses
– Retrovirus (alpha, gamma)
– Replication defective (does not produce viral infection)
– Contain viral oncogene ( transform cells in culture )
• Non acute transforming viruses
– retrovirus (alpha,beta,gamma)
– replication competent (cause viral disease)
– lack viral oncogene (high level of infection months before tumor )

12. Events that must occur before oncogenesis
• Establishing persistent infection
• Evades host immune response
• Immunosuppression
• Host cell susceptibility
• Retention of viral nucleic acid inside the host cells

13. Establishing persistent infection
• Prolonged interaction between the tumor virus and the host cell is
essential for oncogenesis to develop
• Possible only when the tumor virus establishes a longterm persistent
infection in host cells.

14. Evades host immune response
• Host immune response plays an important role in viral clearance.
• Tumor virus follows various evasion mechanisms to bypass the host immune
response, which are as follow
– By restricting the expression of viral genes which go unnoticed by the immune
cells (e.g. EBV in B cells)
– Infecting the sites that are relatively inaccessible to immune responses (HPV
infecting epidermis)
– Undergoing mutation of certain genes that allows the virus to escape from the
host cellular and humoral responses (HIV).
– Infection and suppression of essential immune cells (CD4 T cell by HIV).

15. Immunosuppression
• Host allows the cancer cells to proliferate and escape the host
immune response
• Immunosuppressed organ transplant recipients and HIVinfected
individuals are at increased risk of EBV and HPV associated
malignancies.

16. Host cell susceptibility
• Host cells may be permissive or non-permissive for replication of a given virus.
– Permissive cells support viral growth and replication of a progeny virus; non-
permissive cells do not.
– Non-permissive cells - host cells that either do not have surface receptors for
viral attachment or do not support the viral replication or the release of virus
progeny.
• Risk of oncogenicity is more when a non-permissive cell is infected by a tumor
virus.

18. Retention of viral nucleic acid inside the host cells
• Essential to maintain a stable genetic change that occurs in a tumor cell.
• DNA copies of tumor viruses (both DNA & RNA tumor viruses) are
integrated within the host cell chromosome.
• RNA of retroviruses get reverse transcribed to DNA
• Hepatitis C virus is an exception, its RNA is neither reverse transcribed,
nor integrated into the host chromosome; but are maintained in the
tumor cells.

19. Viruses Genetic factors of host
irrespective of viral infection
Changes in genome of somatic cells
Activation of growth promoting oncogenes Inactivation of cancer suppressor genes
Expression of altered gene products and loss of regulatory gene products
Neoplasm
Mechanism of Neoplasm Development

20. Direct Acting Indirect Acting
Loss of normal growth regulation processes, Affection of
DNA repair mechanisms
Genetic instability
Mutagenic phenotype
Acute transforming
viruses possess V–onc
into the host cell
chromosomes.
Oncogenic viruses possess “Transforming
gene”  insert into host DNA  altered
expression of Pre-existing cellular gene
which regulate cell growth (P.T.A.D.)
Mechanism of Oncogenecity
P  Protooncogene
T  Tumor suppressor gene
A Apoptosis regulatory genes
D DNA repair genes

21. Normal C-myc
Acute Transforming Virus
Capture
Mutation
Slow transforming virus
insertion
Over expressionOver expression Normal protein
Over expressed
Normal protein
Acute Vs Slow-transforming Viruses
Over expressed
Mutant protein

22. DNA Viruses
Adenoviridae Types 2, 5, 12 Various solid Tumors
Hepadanavirus Hepatitis B Virus (HBV) Hepatocellular carcinoma
Herpesviridae Epstein-Barr Virus (EBV) Brukitt’s lymphoma,
nasopharyngeal carcinoma
Kaposi sarcoma Herpes Virus
(KSHV) (HHV8)
Kaposi sarcoma
Polyomaviridae SV40, polyoma virus Various solid tumors
Papillomaviridae HPV 6, 11, 16, 18
Bovine papilloma Virus
Papilloma, Carcinoma
Poxviridae Shope Fibromavirus Myxoma, Fibroma
Classification of Oncogenic Viruses

23. Classification of Oncogenic Viruses
Human oncogenic viruses and associated malignancies
RNA oncogenic viurses
Flaviviridae
Hepatitis C Hepatocellular carcinoma
Retroviridae

25. Classification of Oncogenic Viruses
Human oncogenic viruses and associated malignancies
RNA oncogenic viurses
Flaviviridae
Hepatitis C Hepatocellular carcinoma
Retroviridae
Alpharetroviruses
1 Rous Sarcoma Virus (RSV) Sarcoma
2 Rous Associated Virus (RAV) B-Cell lymphoma, erythroleukemia
3 Avian myeloblastosis virus (AMV) Myeloid/Erythroid leukemia
4 Avian erythroblastosis virus (AEV) Erythroid leukemia
5 Myelocytoma Virus (MC29) Myeloid leukemia

26. Classification of Oncogenic Viruses
Human oncogenic viruses and associated malignancies
RNA oncogenic viurses
Retroviridae
Betaretroviruses
1 Mouse mammary tumor virus
(MMTV)
Mammary crcinoma
2 Jaagsiekte sheep retrovirus Lung carcinoma
Gammaretroviruses
1 Murine leukemia virus (MuLV) Leukemia, Lymphoma
2 Feline leukemia virus Leukemia, lymphosarcoma
3 Feline sarcoma virus Sarcoma
4 Simian sarcoma Virus Sarcoma

27. Classification of Oncogenic Viruses
Human oncogenic viruses and associated malignancies
RNA oncogenic viurses
Retroviridae
Deltaretroviruses
1 HTLV-1 Adult T cell leukemia/lymphoma
2 Bovine Leukemia Virus B cell leukemia
Epsilonretroviruses
1 Walleye dermal sarcoma virus Sarcoma

28. Viruses Causing Human Cancers
Virus Family Virus Human Cancer
Paillomaviridae Human Papilloma Virus Genital Tumors
Squamous cell carcinoma
Oropharyngeal carcinoma
Herpesviridae Epstein-Barr Virus Nasopharyngeal carcinoma
Burkitt’s lymphoma
Hodgkin disease
B cell lymphoma
Human Herpes Virus 8 Kaposi Sarcoma
Hepadnaviridae Hepatitis B Virus Hepatocellular Carcinoma
Flaviviridae Hepatitis C Virus Hepatocellular Carcinoma
Retroviridae Human T cell Lymphoma Virus Adult T Cell lymphoma
Human immunodeficiency virus AIDS related malignancies

29. Properties of Transformed Cells
• Changes in morphology
– Change in cell morphology
– Chromosomal alteration
• Changes in cell metabolism
– Increased rate of growth
– Increased metabolic activity
• Changes in growth characters
– Loss of cell contact inhibitions
– Formation of microtumors
– Capacity to divide indefinitely in
cultures
• Changes in antigens
– Appearance of new viral specific
tumor Ags
– Loss of surface Ags

30. Tumor Viruses
DNA Viruses
Viral Oncoprotein Expression Viral Oncogene
RNA Viruses
Inactivation of Tumor Supreesor Genes Proto-Oncogene
conversion
Transforming
Proviral Insertion
Near Cellular
Oncogene
Non Transforming

31. DNA Viruses
Hepatitis B Virus (HBV)
Human Papillomavirus
Adeno Virus

32. HPV (Human Papilloma Virus)
• Small
• Non-enveloped
• Virion –Icosahedral
• Genome – double stranded ,circular
DNA

33. Epidemiology
– HPV induced cervical cancer is 2nd most common cancer worldwide
– 16% of all female cancers are linked to HPV
– Papilloma virus is found in 90% of women with cervical cancers

34. HPV Diseases
• Genital HPV is a very common STI  usually causes no symptoms & goes away by
itself  sometimes causes serious illness.
• HPV is responsible for
– Almost all cases of genital warts and cervical cancer
– 90% of anal cancers
– 65% of vaginal cancers
– 50% of vulva cancers
– 35% of penile cancers
– 60% of oropharyngeal cancers (cancers of the back of the throat, including the
base of the tongue and tonsils).
– 4 out of 5 people have at least one type of HPV at some time in their lives. It
is sometimes called the “common cold” of sexual activity.
– HPV infects both men and women.

36. HPV: Symptoms
• Though most HPV infections go away on their own, some HPV infections
persist. HPV infections that don’t go away can cause changes in the cells in
the infected area, which can lead to genital warts or cancer.
• Genital warts usually appear as a small bump or groups of bumps in the
genital area. They can be small or large, raised or flat, or clustered like a
small piece of cauliflower. A healthcare provider can usually diagnose
warts by looking at the genital area.

37. • Cervical cancer usually does not have symptoms until it is quite advanced and
hard to treat. For this reason, it is important for women to get regular screening
for cervical cancer. Screening tests can find early signs of disease so that problems
can be treated before they ever turn into cancer.
• Other cancers caused by HPV might not have signs or symptoms until they are
advanced. These include cancers of the vulva, vagina, penis, anus, and cancers of
the back of the throat, including the base of the tongue and tonsils (oropharynx).

38. Diagnosis
• The Pap test can find abnormal cells on the cervix so that they can be
removed before cancer develops. Abnormal cells often become normal over
time, but can sometimes turn into cancer. These cells can usually be
treated, depending on their severity and on the woman’s age, past medical
history.
• An HPV DNA test, which can find certain HPV types on a woman's cervixnd
other test results.

39. Herpes Virus
• HSV & CMV  to transform cultured cells
• HSV-2  cancer of uterine cervix
• HSV-1  cancer of lip

40. • HSV-8  Kaposi’s sarcoma
• CMV  Kaposi’s sarcoma and carcinoma of prostate

41. Epstein-Barr Virus
• Associated with Burkitt’s lymphoma &
nasopharyngeal carcinoma
• In children whose immune system is
immunocompromised.
• Cells  grow indifinetly  carry EB virus  expresss  Ag 
EBNA (Epstein Barr neucleic antigen)  specific to virus
Lymphocytes Lymphoblast
Transformation

42. Hepatitis B Virus
• Causes Hepatocellular Carcinoma.
• Tumor cells contain Hepatitis B Virus DNA
Poxvirus
• Yaba virus  benign histiocytoma in monkey
• Shope fibroma viruses  fibromas in rabbits
Adenovirus
• Some types (12, 18, 31)  sarcomas in hamsters, not associated with human cancer.

43. RNA Oncogenic Viruses
• All oncogenic RNA viruses except
Hepatitis C Virus belongs to the family
Retroviridae but all retroviruses are not
oncogenic.
• Mainly responsible for leukemias and
sarcomas in their hosts.
• Hepatitis C virus has been associated
with primary hepatocellular carcinoma.

44. The Avian Sarcoma Leukosis Complex
• Are antigenically related viruses which induce avian leukosis (lymphomatosis,
myeloblastosis and erythroblastosis viruses) or sarcoma in fowls (Rous sarcoma
virus).
Murine Leukosis Viruses
• Murine leukemia and sarcoma viruses.
Mammary Tumor Virus of Mice
• Higher natural incidence of breast cancer.
• Used to be known as the “Bittner virus” or “milk factor”.
• Mammary cancer develops only in susceptible strains of mice, after a latent period
of 6-12 months.

45. Leukosis-Sarcoma Viruses of other animals
• Number of viruses have been isolated from leukosis and sarcomas in
various species of animals like cat, rat, guinea pig, hamster and monkey.
Human T cell Leukemia Viruses (HTLV)
• Produce T cell leukemia in human beings.
• HTLV-1 causes T-cell leukemia
• HTLV-2 induces hairy leukamia of T-cell type.

46. Viruses Associated Cancers
DNA Viruses
Human papilloma viruses Genital (cervical, vulvar, penile) warts, may progres to
carcinoma
Epstein-Barr virus (EBV) Nasopharyngeal carcinoma, Burkitt’s lymphoma, B-
cell lymphoma
Human herpes 8 (HHV-8) Kaposi’s sarcoma
Hepatitis B Virus (HBV) Primary hepatocellular carcinoma
Merkel Cell polyomavirus Merkel cell carcinoma
RNA Viruses
Human T cell leukamia virus
(HTLV-1)
T-cell leukemia/lymphoma
Hepatitis C virus (HCV) Primary hepatocellular carcinoma