Describes interaction between host cell and oncogenic viruses

1. Oncogenic virus-host cell interaction
Mousumi Bora
P-1893
Division of Virology
Indian Veterinary Research Institute

2. Contents
Oncogene
History
Oncogenic viruses
Interaction between oncogenic viruses and host cell
Mechanism of oncogenicity of different viruses

3. Oncogenes
 An oncogene is a kind of abnormal gene that predisposes cells to
develop into cancers
 Oncogenes are altered in a way that keeps them stuck in a state of
constant activity
 That uninterrupted action helps drive the uncontrolled growth that
underlies tumors
 Oncogenes can be turned on by inherited changes or by cancer-
promoting agents

4. History of Oncogenes
 The first theory of oncogenes was given by Danish physicist Niels
Henrik Arley, but was rejected
 Later on the term "oncogene" was rediscovered in 1969 by National
Cancer Institute scientists, George Todaro and Robert Heubner
 Oluf Bang and Vilhelm Ellerman in
1908 first show that avian erythro-
blastosis could be transmitted by
cell-free extracts

5. History of Oncogenes cont..
 Subsequently confirmed for solid tumors in chickens in 1910-1911 by
Peyton Rous
 His discovery earned him a Nobel Prize in 1966
 The first confirmed oncogene was discovered in 1970 and was termed
src
 In 1964, Anthony Epstein, Bert Achong and Yvonne Barr and
identified the first human oncovirus from Burkitt lymphoma cells
 The first human retrovirus was discovered by Bernard Poiesz and
Robert Gallo at NIH and Mistuaki Yoshida and coworkers in Japan

6. Oncogenic viruses
 Viruses that produce tumours in their natural host / experimental
animals
OR which induce malignant transformation of cells on culture
Features of viral oncogenesis
 Cause cancer in humans and animals
 Long latency between viral infection and tumorigenesis
 Modulate growth control pathways in cells
 Presence of viral markers in tumour cells

7. Oncogenic proteins
 Viral Oncogenic proteins can
mimic
 Cellular Signaling Molecules
 Alteration of the Production or
Activity of Cellular Signal
Transduction Proteins
 Alter Cellular Signaling
Pathways
 Viral adapter proteins
 Disruption of Cell Cycle
Control Pathways

8. Conversion of Proto-oncogene to Oncogene

9. Oncogenic viruses cont..
TAXONOMIC
GROUPING
EXAMPLES PRIMARY TUMOR TYPES
RNA VIRUSES
1.Flaviviridae Hepatitis C virus Hepatocellular carcinoma
2.Retroviridae
Alpharetroviruses Rous sarcoma virus(RSV) Sarcoma
Rous associated virus(RAV) B-cell lymphoma,
Erythroleukemia
Avian myeloblastosis virus (AMV) Myeloid/ erythroid leukemia
Avian erythroblastosis virus (AEV) Erythroid leukemia
Myelocytoma virus (MC29) Myeloid leukemia
Betaretroviruses Mouse mammary tumor
virus(MMTV)
Mammary carcinoma
Jaagsiekte sheep retrovirus Lung carcinoma

10. Oncogenic viruses cont..
Gammaretroviruses Murine leukemia virus (MuLV) Leukemia, lymphoma
Murine sarcoma virus (MuSV) Sarcoma
Feline leukemia virus Leukemia, lymphosarcoma
Feline sarcoma virus Sarcoma
Simian sarcoma virus Sarcoma
Deltaretroviruses Human T lymphotropic
virus(HTLV)
Adult T cell leukemia
Bovine Leukemia virus B cell leukemia
Epsilonretroviruses Walleye dermal sarcoma virus Sarcoma

11. Oncogenic viruses cont..
DNA VIRUSES
1.Adenoviridae Types 2,5,12 Various solid tumours
2. Hepadnavirus Hepatitis B virus (HBV) Hepatocellular carcinoma
3.Herpesviridae Epstein-Barr virus(EBV)
(HHV4)
Burkitt’s lymphoma,
nasopharyngeal carcinoma
Kaposi sarcoma Herpes
virus (KSHV) (HHV8)
Kaposi sarcoma
4.Polyomaviridae SV40, Polyoma virus Various solid tumors
5.Papillomaviridae HPV 6,11,16,18
Bovine papilloma virus
Papilloma, carcinoma
6.Poxviridae Shope fibroma virus Myxoma, fibroma

12. Interaction between oncogenic viruses and host cell
Persistent infections
 Chronicity of the infections modulate growth control mechanisms
Latency of viral genome
Episomal copies of viral genome are maintained in transformed cells
Viral genome is integrated into host cell genome
Tumorigenesis after latent period
Evasion of host immune response
Restricted expression of viral genome (EBV )
Infection of sites inaccessible to immune response (HPV)
Mutation of viral antigens (EBV)
Exhibition of marked tissue specificity

13. Mechanism of Oncogenecity
DIRECT INDIRECT
Introduction of new
‘Transforming gene’
into the cell
Alteration of expression of
pre-existing cellular gene
 Loss of normal growth regulation processes
Affection of DNA repair mechanisms
Genetic instability
Mutagenic phenotype

14. Mechanism of Oncogenecity cont..

15. Cancer Hallmark activation by Oncoviruses
 Oncogenic viruses when overcome the ability of the host to
maintain homeostasis, they trigger cellular changes ultimately
leading to cancer.
• Signaling mimicry: Viruses encode proteins that are able to
subvert the host-signalling mechanisms that regulate cell growth
and survival
• Effects on the DNA damage response (DDR) : Recognition of
viral genomes or replicative intermediates by the host leads to
induction of DDR
 As a consequence, host cells acquire genetic instability, which
increases their mutation rate and accelerates acquisition of
oncogenic host chromosomal alterations

16. Cancer Hallmark activation by Oncoviruses cont…

17. Cancer Hallmark activation by Oncoviruses cont..
• Chronic inflammatory responses to persistent viral infection:
 Inflammation drives reactive oxygen species (ROS) generation that
promotes the acquisition of mutations
 Observed in chronic HBV and HCV infections
Hepatitis, fibrosis, cirrhosis, and
eventually
hepatocellular carcinoma

18. Cancer Hallmark activation by Oncoviruses cont..

19. Epstein-Barr Virus
 EBV is an oncogenic gamma-1 herpesvirus
 Implicated in several lymphoid malignancies, including several B, T,
and NK cell lymphomas and epithelial carcinomas
EBV mimics B cell proliferative and survival signaling
Replicate its genome while remaining latent and
immune-silent in the host B cells
Establishing lifelong persistence

20. Molecular Mechanisms of EBV Oncogenesis
 The latency pattern of EBV are associated with specific
lymphoma subtypes:
Latency I
Latency II
Latency
III
Burkitt’s
lymphoma
Hodgkin’s disease
and nasopharyngeal
carcinoma
Most AIDS-Associated
Non-Hodgkin’s
lymphomas and
lymphoproliferative
disorder

21. Molecular Mechanisms of EBV Oncogenesis cont..
 Latency I
1
• EBNA1 function in latency is to leash EBV episomes
to the host chromosome allowing their retention and
segregation during cell division
2
• EBNA1 is essential for lymphoma survival by
preventing cell death
3
• Increase genomic instability by regulating RAG-1
and RAG-2 and increasing ROS
Burkitt’s lymphoma

22. Molecular Mechanisms of EBV Oncogenesis cont..
Burkitt’s
lymphoma

23. Molecular Mechanisms of EBV Oncogenesis cont..
 Latency II
 EBV oncogenes ( LMP1 and LMP 2A) mimics key survival and
proliferative signals in B cells
LMP1 mimics an active CD 40 receptor
Hodgkin’s Disease and Nasopharyngeal Carcinoma
Recruits TRAFs and
TRADD
NF-κB pathway
Activation
Viral and Non-viral
lymphomagenesis

24. Molecular Mechanisms of EBV Oncogenesis cont..
 Latency III
Latency III expresses full oncogenic component of nuclear proteins
EBNA2, EBNA3A, EBNA3B, EBNA3C, LMP-1 and LMP-2A
EBNA2 (Nuclear phosphoprotein)
Associate with RBP-Jk
Notch Target genes
Non-viral lymphoid malignancies
AIDS associated Non-Hodgkin’s Lymphomas and Post-
transplant lymphoproliferative disorder
Activation
Deregulated Notch
signaling drives

25. Molecular Mechanisms of EBV Oncogenesis cont..

26. Human Papillomavirus
 Approximately 5% of all human cancers worldwide are caused by
HPVs
 High-risk HPV E5, E6 and E7 genes encode potent oncoproteins
 Dysregulated HPV E6 and E7 expression as a consequence of
integration of viral sequences into the host genome
 Due to epigenetic alterations of the viral genome

27. Spectrum of cancer hallmark of HPV

28. Hepatitis B and C virus
 HBV and HCV are major etiological agents of hepatocellular
carcinoma (HCC)
 Both viruses establish chronic infections, and when accompanied by
hepatitis hepatocellular destruction triggers regeneration and scarring
(fibrosis), which can evolve into cirrhosis and HCC
 The pathogenesis of HCC is a combination of direct and indirect
mechanisms
Chronic oxidative damage
that promotes the
development of mutations
Immune-mediated
inflammation

29. Hepatitis B and C virus cont..
Direct mechanism :
 HBV-encoded X antigen (HBx) and HCV-encoded core,
nonstructural protein 5A (NS5A) and NS3 directly promote HCC by
altering host gene expression
Indirect mechanism :
 Both HBV and HCV evade growth suppression and avoid immune
destruction by blocking apoptosis
 Apoptosis is triggered by virus-generated oxidative stress (intrinsic
apoptosis) and by immune-mediated apoptosis (extrinsic apoptosis)
 HBx blocks the activation of mitochondrial antiviral signaling protein
 HBx prevents extrinsic apoptosis triggered by TNF-α, TGF-ß, and Fas
by blocking caspases-8 and -3 and activating NF-κ B

30. Hepatitis B and C virus cont..

31. Hepatitis B and C virus cont..

32. Human T cell lymphotropic virus 1
 HTLV-1, the first described human lymphotropic retrovirus
 Etiologic agent for adult T cell leukemia/lymphoma (ATL)
 HTLV-1-driven oncogenesis is a two step process
Tax-dependent
stage
Tax transactivator
induces T cell
proliferation
Switches to
a Tax-independent stage
Tax-independent
stage
Tax is repressed
or deleted
Oncogenic process is
driven by the
HTLV-1 bZip (HBZ)
protein and its RNA

33. Human T cell lymphotropic virus 1 cont..

34. Kaposi Sarcoma Herpesvirus
 KSHV or human herpesvirus-8 (HHV-8) is a ɤ2-herpesvirus
 Causal agent of Kaposi’s sarcoma (KS)
 KS is characterized by the proliferation of infected spindle cells
of vascular and lymphatic endothelial origin
 KSHV can infect a variety of cells
including endothelial lineage,
monocytes, and B cells

35. Kaposi Sarcoma Herpesvirus cont..
 KSHV undergo latent or lytic stages of replication
 KSHV replicates along with the host by expressing KSHV latency-
associated nuclear antigen (LANA)
 Tethers the KSHV episome to the host chromosome, thus assuring its
maintenance and segregation during host cell division
 LANA inhibits both the p53 and the pRB tumor suppressor pathways
Allowing the infected cell Insensitive to antigrowth signals
Avoiding cell-cycle arrest and
Promoting genetic instability

36. Kaposi Sarcoma Herpesvirus cont..

37. Paracrine oncogenesis of KSV

38. Therapeutic and Preventive approaches

39. THANK YOU