oncogenic viruses dna viruses herpesviridae –human herpes virus 8 ( hhv8) a.k.a kaposi’s sarcoma...
TRANSCRIPT
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)
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).
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).
Burkitt’s lymphoma
Nasopharyngeal carcinoma
Hodgkin’slymphoma
40-50% of patients are
EBV seropositiveNPC tissue stained for the presence of EBV late antigens.
Trends in Molecular Medicine Volume 10, Issue 7 , 1 July 2004, Pages 331-336
EBV infection and Burkitt’s lymphoma
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
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,
Copyright © 1998 - 2000 David Reznik, D.D.S. All Rights Reserved
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
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
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
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
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