Oncogenic viruses

DNA viruses• Herpesviridae

– Human Herpes Virus 8 (HHV8) a.k.a Kaposi’s sarcoma associated virus

– Epstein-Barr virus (EBV)

• Papovaviridae – human papilloma virus

(HPV)

• Hepadnaviridae– hepatitis B virus-(HBV)

RNA viruses• Flaviviridae

– (hepatitis C virus HCV)

• Retroviridae – Human T-cell

lymphotropic virus (HTLV type I)

Why are they oncogenic?Viral genomes show the

presence of several human gene homologues that are responsible for cellular transformation

e.g. v-myc and c-myc (myc oncogene) or vIL6 and IL6 (interleukin 6)

Overview of viral replication

Human Herpes Virus 8 (HHV8) or Kaposi’s sarcoma associated virus KSHV

Herpes virus family

Type 1 - causes ‘cold sores’ on lips (~90% of population) Type 2 - sexually transmitted disease that causes "cold sores" on the genitals (~ 25% of US adults).

Human Herpes Virus 8 (HHV8) a.k.a Kaposi’s sarcoma associated virus HHV8 endemic

regions

Kaposi’s sarcoma

HHV8 and transformation

EBV- Epstein Barr Virusmost potent transforming agent,widespread in all human populationsusually carried as an asymptomatic persistent infection.

virus sometimes associated with the pathogenesis of certain types of lymphoid and epithelial cancers, including Burkitt lymphoma (BL), Hodgkin disease and nasopharyngeal carcinoma (NPC).

EBV associated cancers

Burkitt’s lymphoma

Nasopharyngeal carcinoma

Hodgkin’slymphoma

40-50% of patients are

EBV seropositiveNPC tissue stained for the presence of EBV late antigens.

in vivo interactions

between EBV and host cells

Trends in Molecular Medicine Volume 10, Issue 7 , 1 July 2004, Pages 331-336

EBV infection and Burkitt’s lymphoma

Nasopharyngeal carcinoma (NPC)

EBV and pathogenesis of NPC

aetiology of several different lymphoid and epithelial malignancies.

EBV-encoded latent genes induce B-cell transformation in vitro by altering cellular gene transcription and constitutively activating key cell-signalling pathways.

EBV exploits the physiology of normal B-cell differentiation to persist within the memory-B-cell pool of the immunocompetent host.

Summary of EBV

Putative life cycle of HBV

Human papilloma virus (HPV)90% of cervical cancers contain HPV DNA.

4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounted for about 80% of the HPV-positive cancers.

HPV-16 most common type of HPV found in cervical cancers.

HPV-16 is the most common type in squamous cell cancers.

HPV-18 is the predominant type in adenocarcinomas,  

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Regions of stratified epithelium where HPV is maintained and amplified

Transforming activity of HPV16 is associated with mainly E6 and E7proteins

E6 and E7 are multifunctional proteins that can increase cell proliferation and survival by interfering with tumour suppressor activity.

Cancer transformation

Cancer transformation

RNA viruses

• Unstable RNA genome• prone to mutations • Generates genetic diversity and

escape antiviral therapy• Can be oncogenic (e.g.hepatitis C

virus HCV)

hepatitis C virus HCVAffects 3% of global population Infects primarily hepatocytes50-80% of infected individuals go on to develop hepatocellular

carcinoma (HCC)At least 6 genotypes known

HCV life cycle

What causes hepatocellular carcinoma?

• Current hypothesis is HBV and HCV infection

• HBV integrate into genome and a protein Hbx is known to cause HCC

• HCV does not integrate into the genome but can interact with host proteins and cause an inflammatory response, which can transform cells

e.g. HCV proteins NS3 and NS5A can disrupt transcription factors leading to proliferation and inhibition of apoptosis

Human Immunodeficiency Virus HIV

HIV life cycle

See animation at http://www.roche-hiv.com/home/home.cfm

HIV genome3 structural genesgag (group specific antigen) encodes matrix, capsid, nucleocapsid proteinspol (polymerase) encodes reverse transcriptase, integrase, proteaseenv (envelope) encodes surface & transmembrane proteins6 regulatory genesrev (regulatory virus protein)tat (transactivator)nef (negative regulatory factor)vif, vpr, vpu, env (envelope) encodes surface & transmembrane protein

Course of HIV infection

Antiretroviral or anti HIV therapyAll approved anti-HIV drugs attempt to block viral replication

within cells by inhibiting either RT or HIV protease.

• Nucleoside analogues mimic HIV nucleosides preventing DNA strand completion e.g. Zidovudine (AZT), ddI, ddC, Stavudine

• Non nucleoside RT inhibitors (NNRTI) e.g Delavirdine and Nevirapine

• Protease inhibitors block active, catalytic site of HIV protease

Multidrug therapy

• HAART (highly active antiretroviral therapy) usually consists of triple therapy including

– 2 nucleoside analogues + 1 protease inhibitor

– 1 non nucleoside RT inhibitor + 1(2) prot. inhibitor

EBV genome

EBV-encoded nuclear antigen 2 (EBNA2)

latent membrane protein 1

LMP2