Download DNA viruses EBV- Epstein Barr Virus

Oncogenic 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
Is cancer infectious?
1909, Peyton Rous discovers sarcoma-inducing agent in
chickens
Figure 3.1; 3.2 The Biology of Cancer (© Garland Science 2007)
Normal cells infected with certain viruses
can be transformed
Figure 3.7a The Biology of Cancer (© Garland Science 2007)
Viral transformation can induce cellular
changes including tumourigenicity
Table 3.2 The Biology of Cancer (© Garland Science 2007)
Approximately one in six human cancers is
caused by a human tumour virus!!
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)
Overview of viral replication
Genome replication
DNA viruses
RNA viruses
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 oncogenes
e.g. c-src/v-src ; v-myc/c-myc ; vIL6/ IL6 (interleukin 6)
Insertion of viral sequences into host
DNA carrying the proto-oncogene
E.g. Insertion of ALV into c-myc protooncogene
Figure 3.23a The Biology of Cancer (© Garland Science 2007)
v-myc and c-myc (myc oncogene)
Table 3.4 The Biology of Cancer (© Garland Science 2007)
DNA viruses
Herpesviridae
• Human Herpes Virus 8
(HHV8) a.k.a Kaposi’s
sarcoma associated
virus
• Epstein-Barr virus
(EBV)
EBV- Epstein Barr Virus
most potent transforming agent,
widespread in all human populations
usually 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
lymphoma
Nasopharyngeal
carcinoma
NPC tissue stained for the
presence of EBV late
antigens.
Hodgkin’s
lymphoma
40-50% of patients
are
EBV seropositive
EBV 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 vivo interactions between EBV and host
cells
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.
Human papilloma virus (HPV)
90% of cervical cancers contain HPV DNA.
4 types (HPV-16, HPV-18, HPV-31, and HPV-45) accounts
for ~ 80% of HPV-positive cancers.
HPV-16 & 18 most common type of HPV found in ~70% of
cervical carcinomas.
HPV-6,11 : common in genital warts
Copyright © 1998 - 2000 David Reznik, D.D.S. All Rights Reserved
HPV 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 genome
HPV 16 produces only eight proteins
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)
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
Development of cancer
E6 and E7 proteins inactivate tumour suppressor
proteins p53 and pRB
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.
Inactivation of pRB by E7
Gardasil© (Merck):
quadrivalent recombinant vaccine against HPV types 6, 11, 16
and 18
• 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.
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 viruses
• Unstable RNA
genome
• prone to
mutations
• Generates
genetic diversity
and escape
antiviral therapy
• Can be
oncogenic
(e.g.hepatitis C
virus HCV)
Retroviral replication
Figure 3.17 The Biology of Cancer (© Garland Science 2007)
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
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
What causes hepatocellular 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 cycle
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
• Most people infected with HHV8 do not get KS
• Immunosuppressed individuals are susceptible
• Viral homologues of several human proteins (e.g. v-cyc, vIL6)