Transcript powerpoint

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 Virus
most potent transforming agent,
widespread in all human populations
usually 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
NPC tissue stained for the
presence of EBV late
antigens.
Hodgkin’s
lymphoma
40-50% of patients
are
EBV seropositive
in vivo
interactions
between EBV
and host cells
EBV infection and Burkitt’s lymphoma
Trends in Molecular Medicine
Volume 10, Issue 7 , 1 July 2004, Pages 331-336
Nasopharyngeal carcinoma (NPC)
EBV and pathogenesis of NPC
Summary of EBV
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-Bcell pool of the immunocompetent host.
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,
Copyright © 1998 - 2000 David Reznik, D.D.S. All Rights Reserved
Regions of stratified epithelium where
HPV is maintained and amplified
Cancer
transformation
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 HCV
Affects 3% of global population
Infects primarily hepatocytes
50-80% 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 genome
3 structural genes
gag (group specific antigen)
encodes matrix, capsid,
nucleocapsid proteins
pol (polymerase) encodes
reverse transcriptase,
integrase, protease
env (envelope) encodes
surface & transmembrane
proteins
6 regulatory genes
rev (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
EBV genome
EBV-encoded nuclear antigen 2 (EBNA2)
latent membrane protein 1
LMP2