ONCOGENIC VIRUSES
MasikaM.M.
Outline
Oncogenic Mechanisms overview
Oncogenic viruses
Specific oncogenic mechanisms:
HBV, HCV, HPV, HHV-8, EBV, HTLV
Related cancers:
Hepatoma, Ca Cervix, Kaposi sarcoma, Burkitts lymphoma, Adult T-cell Lymphoma
Keyterms
Cancer
Oncogene
Proto-oncogene
Tumor suppressor gene
Transformation
Requirementsfortumorigenesis
Independence of proliferation signals
Evasion of apoptosis
Insensitivity to anti-growth signals
Unlimited replicative potential
Ability to invade and metastasize
Ability trigger sustain and angiogenesis
ViralOncogenicMechanisms
Oncoviruses:
Carry
a copy of genes that usually stimulate cell growth OR
Alter the expression of hosts genes that normally inhibit cell
growth
Approx.
20% of cancers in women and 10% of cancers
in men are virus-associated
Sub Saharan Africa
Oncogenicviruses
DNA Oncoviruses
Adenoviruses
Herpesviruses
Human papillomaviruses
Hepadnaviridae
RNA Tumor Viruses
Retroviruses
Flavivirus (HCV)
Virusassociatedcancers
Virus
Cancer
Human herpes virus 8 (HHV-8)
Kaposi Sarcoma
Epstein-Barr Virus - EBV (HHV-4)
Burkitt Lymphoma
Nasopharyngeal carcinoma
Cervical cancer
Other anogenital cancers
Human papillomavirus (HPV)
Hepatitis B Virus (HBV)
Hepatocellular carcinoma
Hepatitis C Virus (HCV)
Hepatocellular carcinoma
Human T-lymphotropic virus (HTLV)
Adult T-cell Leukemia
Humanpapillomavirus
Small, naked virus (8 kilo bases), circular dsDNA,
Family: Papillomaviridae
Classified as high or low risk
High risk genotypes: HPV 16, 18, etc.
Low-risk genotypes: HPV 6, 11, etc.
HPV
Linked to nearly all cervical cancers
90% clear HPV within 2yrs after infection
Less than 1% develop Ca Cervix (takes 10-30 years)
Also linked to other anogenital cancer
CERVICAL CANCER
Cervicalcancer
Virtually all cases are attendant to persistent HPV infection
World: 530,000 cases annually, 275,000 deaths p.a.
77% of all cases and 88% of all deaths occur in LMICs
Kenya: 5000 cases p.a.; Mortality = 50%
Developed countries have reduced Ca cervix deaths by up to
80% through screening services
MechanismofOncogenesis
HPV is integrated into the host genome
HPV genome has 2 oncogenes: E6 and E7
E6 proteins bind p53 blocking apoptosis
E7 proteins bind retinoblastoma gene (Rb):
pRB represses gene transcription
Its suppression induces DNA synthesis in keratinocytes
Harald zurHausen
HPV GENOME
EpsteinBarrVirus(EBV)
Human herpes virus 4 (HHV-4)
Family: Herpesviridae, Subfamily: Gammaherpesvirinae,
Genus: Lymphocryptovirus
High prevalence (90% of people infected)
Little or no symptoms
May cause infectious mononucleosis
Transmitted in saliva
EBVassociatedcancers
Associated with:
Burkitt Lymphoma
Nasopharyngeal carcinoma
Others: Hodgkins Lymphoma, Non-Hodgkins Lymphoma in HIV/AIDS
Infection is common but cancer is rare
Cancer is associated with immunosuppression
BurkittLymphoma
Common in East and central Africa
Types: Endemic, sporadic, HIV-associated
All cases have c-myc translocation but not all cases have EBV
Translocation
Translocation of c-myc gene from chromosome 8 to 14
New location is next to an enhancer for Ig synthesis
Causes over-expression of c-myc
EBV is thought to be one of the causes of this translocation
Translocation(t8:14)
EBV:oncogenesis
The virus is present in cancer cells as cccDNA
Two viral proteins are implicated: LMP and EBNA
LMP (Latent Membrane Protein) inserted into host cell membrane, acts as a
Growth Factor Receptor causing unregulated growth
EBNA (EBV Nuclear Antigens) alter activity of tumor suppressors e.g. p53, pRb
EBNAs also deregulate the expression of c-myc oncogene
Nasopharyngealcarcinoma
Common in the Far East esp. in men
EBV transforms the cells through signaling pathways that
lead to proliferation and prevent apoptosis
Humanherpesvirus8(HHV 8)
Family: Herpesviridae; Subfamily: Gammaherpesvirinae;
Genus: Rhadinovirus
Enveloped, dsDNA, linear genome
Very common esp. in ssAfrica (60% seroprevalence)
Causes Kaposi sarcoma in immunosuppression esp. HIV
HHV8associatedcancers
Kaposi sarcoma
Proliferation of (vascular) endothelial cells
B cell lymphomas:
Multicentric CastlemansDisease
Primary effusion lymphoma
Kaposisarcoma
HHV8:Mechanismofoncogenesis
HHV-8 is present in most KS tumour cells, expressing viral
latent proteins and viral lytic proteins
Viral latent proteins:
Enhance cell proliferation and prevent apoptosis
e.g. FLICE-inhibitory protein and Latency-associated Nuclear Antigen (LANA)
Viral lytic proteins:
Trigger secretion of cytokines and growth factors
E.g. viral BCL-2, viral G-protein coupled receptor (vGPCR)
Hepatocellularcarcinoma(HCC)
Has multiple etiologies
50% of all HCC cases are associated with HBV
25-30% are associated with HCV
HepatitisBvirus
Family: Hepadnaviridae
Partially dsDNA genome
Persistent HBV infection
causes chronic inflammation
HBx gene key in
oncogenesis
HBV:Hepatocarcinogenesis
HBV genome is integrated in most HCC cells
HBx gene interferes with apoptosis and chromosomal
stability
Alter several signaling pathways:
p53, Wnt/B-catenin pathway, cytokine pathways, etc.
HepatitisCVirus
Family: Flaviviridae
(+)ssRNA virus
Core and E1/E2 genes
play a role in oncogenesis
HCV:Hepatocarcinogenesis
HCV does not integrate into host genome
HCV-associated carcinoma usually follows cirrhosis
HCV Core interferes with cell signaling pathways
E1 and E2 proteins interfere with cytokine signaling
HumanTLymphotropicVirus(HTLV)
A retrovirus
Infects Human T-Cells
2-5% of infected persons develop Adult T-cell Leukemia
Transmission: Sexual contact, blood transfusion, needlesharing, breastfeeding
Endemic in Japan, Americas, Caribbean, West Aftica
HTLV1:MechanismofOncogenesis
All Retroviruses have 3 primary genes - gag, pol & env
Some express accessory genes
HTLV express several accessory genes e.g. tax
tax gene enhances viral gene transcription &replication,
and proliferation of infected cells
Cytotoxic T-lymphocytes target cells expressing tax
Some infected cells evade CTLs by stopping tax
expression thus continue proliferation
Summary
Virus Cancer
HHV-8
EBV
HPV
HTLV
Mechanism
Kaposi Sarcoma
(LANA, vGPCR)
Enhances cell proliferation
Prevents apoptosis
Secretion of Cytokines & Growth Factor
Burkitts Lymphoma
Translocation of c-myc (t.8:14) leading
Nasopharyngeal carcinoma to its over-expression
Cervical cancer
Bind p53 (E6)- Blocking apoptosis
Bind pRb (E7)- inducing replication
Adult T-cell Lymphoma
Enhanced transcription, replication and
proliferation of infected cells (Tax gene)
HBV
Hepatocellular carcinoma
HCV
Hepatocellular carcinoma
Inactivation of tumor suppressors
Activation of proto-oncogene
Chronic inflammation/ Cytokine release
References
Virology Principles & Applications J. Carter & V. Saunders
www.microbiologybook.org
PUBMED - http://www.ncbi.nlm.nih.gov/pubmed
ICTV Master species list 2014
