Oncogenic virusesOncogenic viruses

Key Concepts• Normal cells infected with certain

viruses can be transformed into cancer cells due to expression or activation of viral oncogenes

• Transformation can result in integration of viral genes or genomes into the host genome

Figure 3.1; 3.2 The Biology of Cancer (© Garland Science 2007)

1909, Peyton Rous discovers sarcoma-inducing agent in chickens

Is cancer infectious?Is cancer infectious?

Figure 3.7a The Biology of Cancer (© Garland Science 2007)

Normal cells infected with certain viruses Normal cells infected with certain viruses can be transformedcan be transformed

Table 3.2 The Biology of Cancer (© Garland Science 2007)

Viral transformation can induce Viral transformation can induce cellular changes including cellular changes including

tumourigenicitytumourigenicity

Approximately one in six human cancers is Approximately one in six human cancers is caused by a human tumour virus!!caused by a human tumour virus!!

Herpesviridae • Human Herpes Virus 8

(HHV8) a.k.a Kaposi’s sarcoma associated virus

• Epstein-Barr virus (EBV)

Papovaviridae human papilloma virus (HPV)

Hepadnaviridaehepatitis B virus-(HBV)

• Flaviviridae (hepatitis C virus

HCV)

• Retroviridae Human T-cell

lymphotropic virus (HTLV type I)

DNA virusesDNA viruses RNA virusesRNA viruses

Overview of viral replicationOverview of viral replication

Genome replication Genome replication

DNA viruses RNA viruses

How does tumourigenicity occur?How does tumourigenicity occur?Viral genomes show the presence of several human

gene homologues (cellular proto-oncogenes)Infective viruses ‘kidnap’ proto-oncogenes which are

then transformed into oncogenese.g. c-src/v-src ; v-myc/c-myc ; vIL6/ IL6 (interleukin 6)

Figure 3.23a The Biology of Cancer (© Garland Science 2007)

Insertion of viral sequences into host Insertion of viral sequences into host DNA carrying the proto-oncogeneDNA carrying the proto-oncogene

E.g. Insertion of ALV into c-myc protooncogene

v-myc and c-mycv-myc and c-myc (myc oncogene) (myc oncogene)

Table 3.4 The Biology of Cancer (© Garland Science 2007)

Herpesviridae • Human Herpes Virus 8

(HHV8) a.k.a Kaposi’s sarcoma associated virus

• Epstein-Barr virus (EBV)

DNA virusesDNA viruses

EBV- Epstein Barr VirusEBV- Epstein Barr Virus

most potent transforming agent,widespread in all human populationsusually carried as an asymptomatic persistent infection (latent).

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

Burkitt’s Burkitt’s lymphomalymphoma

Nasopharyngeal Nasopharyngeal carcinomacarcinoma

Hodgkin’sHodgkin’slymphomalymphoma

40-50% of patients are

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

EBV genome and host cell transformationEBV genome and host cell transformation

EBV-encoded nuclear antigen 2 (EBNA2)

latent membrane protein 1 (LMP1) mimics CD40 receptor

LMP2 mimics the B cell receptor

in vivoin vivo interactions between EBV and host interactions between EBV and host cellscells

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 EBVSummary of EBV

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

4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounts 4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounts for ~ 80% of HPV-positive cancers.for ~ 80% of HPV-positive cancers.

HPV-16 & 18 most common type of HPV found in ~70% of HPV-16 & 18 most common type of HPV found in ~70% of cervical carcinomas.cervical carcinomas.

HPV-6,11 : common in genital wartsHPV-6,11 : common in genital warts

Copyright © 1998 - 2000 David Reznik, D.D.S. All Rights Reserved

HPV life cycleHPV life cycle

• Infection established in basal epithelial layers where viral genome maintained as an episome

• Viral replication occurs in suprabasal layers • Infections are therefore long lasting

Integration into the host genomeIntegration into the host genome

HPV 16 produces only eight proteins HPV 16 produces only eight proteins

E1 Replication of viral DNA; maintenance of viral episome; essential for viral replication and control of gene transcription

E2 Essential for viral replication; repression of E6 and E7

E4 Forms filamentous cytoplasmic networks

E5 Prevents acidification of endosomes; interaction with Epidermal Growth Factor (EGF)

/Platelet-Derived Growth Factor (PDGF)

LCR Origin of DNA replication; regulation of HPV gene expression

Protein Function

L1 Major capsid protein in the virus particle; by itself, L1 can assemble into capsomers and then form virus-like particles (VLPs)

L2 Minor capsid protein in the virus particle; L2 binds to DNA

E6 Destruction of p53 tumor suppressor protein

E7 Inactivation of Retinoblastoma tumor suppressor protein (Rb)

Development of cancerDevelopment of cancer

E6 and E7 proteins inactivate tumour suppressor E6 and E7 proteins inactivate tumour suppressor proteins p53 and pRBproteins p53 and pRB

Transforming activity of HPV16 is associated with mainly E6 and E7proteinsE6 and E7 are multifunctional proteins that can increase cell proliferation and survival by interfering with tumour suppressor activity.

Inactivation of pRB by E7Inactivation of pRB by E7

• To prevent cervical cancers in children aged 9–15 years and women from 16-26 years

• expected to prevent up to 70% of• nearly 100 percent effective in preventing

precancerous cervical lesions, precancerous vaginal and vulvar lesions and genital warts caused by infection with the HPV types 6, 11, 16 or 18 in women between the ages of 16 and 26.

GardasilGardasil©© (Merck): (Merck): quadrivalent recombinant vaccine against HPV types 6, 11, 16 quadrivalent recombinant vaccine against HPV types 6, 11, 16

and 18and 18

References

Chapter 3: Biology of Cancer by RA Weinberg

Optional reading• Oncogenic viruses by Dennis J McCance

www.els.net • Epstein-Barr virus: 40 years on Nature Rev

Cancer 4 (10)757-68 Oct 2004 Young LS, Rickinson AB

• How will HPV vaccines affect cervical cancer? Roden R, Wu TC Nat Rev Cancer. 2006 Oct;6(10):753-63

The following slides are for general interest only (since there

is not enough time to cover all viruses in detail)

Translated as THERE WILL BE NO SPECIFIC

QUESTION ON RETROVIRUSES IN THE EXAM

RNA virusesRNA viruses• Unstable RNA

genome• prone to

mutations • Generates

genetic diversity and escape antiviral therapy

• Can be oncogenic (e.g.hepatitis C virus HCV)

Figure 3.17 The Biology of Cancer (© Garland Science 2007)

Retroviral replicationRetroviral replication

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 therapy

All 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

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

carcinoma (HCC)At least 6 genotypes known

What causes hepatocellular What causes hepatocellular carcinoma?carcinoma?

• HBV and HCV co-infection?• HBV integrates into genome and produces a

protein Hbx, involved in 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

HCV life cycleHCV life cycle

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

Kaposi’s sarcomaKaposi’s sarcoma

HHV8 and transformationHHV8 and transformation• Most people infected with HHV8 do not get KS• Immunosuppressed individuals are susceptible• Viral homologues of several human proteins (e.g. v-cyc, vIL6)