oncogenic viruses key concepts normal cells infected with certain viruses can be transformed into...
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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)