Oncogenic virus-host cell interaction

Oncogenic virus-host cell interaction

Mousumi Bora

P-1893

Division of Virology

Indian Veterinary Research Institute

Contents

Oncogene

History

Oncogenic viruses

Interaction between oncogenic viruses and host cell

Mechanism of oncogenicity of different viruses

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

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

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

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

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

Conversion of Proto-oncogene to Oncogene

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


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


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

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

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

Mechanism of Oncogenecity cont..

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

Cancer Hallmark activation by Oncoviruses cont…

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

Cancer Hallmark activation by Oncoviruses cont..

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

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

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


Burkitt’s

lymphoma


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


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


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

Spectrum of cancer hallmark of HPV

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

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

Hepatitis B and C virus cont..

Hepatitis B and C virus cont..

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

Human T cell lymphotropic virus 1 cont..

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

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

Kaposi Sarcoma Herpesvirus cont..

Paracrine oncogenesis of KSV

Therapeutic and Preventive approaches

THANK YOU

Oncogenic virus-host cell interaction

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