Chapter 34
Oncogenic
Viruses
Dr Sonal Saxena
Dr Arpita Saxena
MECHANISMS OF VIRAL ONCOGENESIS
Oncogenic DNA – Cytomegalovirus
viruses – Hepatitis B virus
– Human Oncogenic RNA
polyomaviruses viruses
– Simian virus 40 – Retrovirus
– Poxvirus – Oncogenes
– Adenovirus – Current trends
– Herpes virus
Viruses that produce tumours in their natural
hosts or in experimental animals or induce
malignant transformation of cells on culture are
known as oncogenic viruses.
Viral infections- 10–20% of human malignancies
Introducti Examples:
Hepatocellular carcinoma (HBV, HCV)
on Cervical cancer (papillomaviruses)
Anaplastic nasopharyngeal carcinomas (EB virus)
Adult cutaneous T cell lymphoma/leukemia
(HTLV-1)
MECHANISMS OF
VIRAL
ONCOGENESIS
Both RNA and DNA viruses are oncogenic
RNA viruses–family Retrovirus.
DNA viruses-herpes viruses and
hepadnaviruses
Transformation of a healthy cell to a malignant
cell is a multistep process and may be partial or
complete
List of oncogenic viruses
Slow transforming viruses: The standard oncogenic
retroviruses, low oncogenic potential, long latent period.
They do not transform cultured cells and are capable of
replicating normally.
Acute transforming viruses: Highly oncogenic, short latent
period of weeks or months. Can transform cells in culture.
Virus They can be :
◦ Replication-defective: Most acute transforming viruses
transforma are unable to replicate normally because they carry on
tion their genome an additional gene, the viral oncogene (V-
onc gene). These can replicate only if co-infected with a
standard helper retrovirus.
◦ Replication-competent: The Rous sarcoma virus, with
oncogenic src can replicate normally because it possesses
the full complement of gag, pol and env genomes.
Not essential for the replication of the virus; mutants that lack these
genes replicate normally without being oncogenic.
Genes closely resembling viral oncogenes are found in normal as well
as cancer cells.
Oncogenes isolated from cancer cells are called cellular oncogenes
Viral (C-onc).
Proto-oncogenes
oncogenes Similar genes found in normal cells, not of viral origin, they appear to
(V-onc) be of host cell origin.
Cellular oncogenes contain introns characteristic of eukaryotic genes,
Cancer gene whereas viral oncogenes do not.
These are widespread in vertebrates and metazoa—from human
beings to fruit-flies.
Well conserved in their genomes.
They code for proteins involved in regulating cell growth and
differentiation.
This is a useful method for the study of oncogenes.
Certain mouse fibroblast cell lines such as NIH 3T3 can
take up foreign DNA, incorporate them into their genome,
TRANSFECTI and express them. This is called transfection.
By this technique, DNA extracted from human tumour
ON cells has been shown to transform 3T3 cells; such
transforming genes have been shown to be identical to
cellular oncogenes.
Anti-oncogenes
A class of genes has been identified in the normal retinoblastoma (Rb) gene, the loss of which
is associated with the development of retinoblastoma in children.
The p53 gene appears to be a tumour suppressor gene with a wide range of effects.
Specific chromosomal deletions, recognised in association with certain types of human cancers
may reflect the loss of tumour suppressor genes.
Malignancy is a stable, heritable change and, as such, should be the result of a modification of
the host cell genome.
Specific chromosomal deletions, recognised in association with certain types of
human cancers may reflect the loss of tumour suppressor genes.
Oncogenic DNA viruses: Viral DNA (or a portion) is integrated with the host cell
genome. As the viral DNA is incomplete or ‘defective’, no infectious virus is
Anti- produced. However, under its influence, the host cell undergoes malignant
transformation.
oncogenes
Oncogenic RNA viruses: In general, retroviruses induce tumours by one of two
mechanisms:
• They may introduce into the cellular genome a new transforming gene
(oncogene).
• They may induce or alter the expression of a pre-existing cellular gene.
Mechanism of Oncogenesis:
DNA virus
The viral DNA (or a portion of it) is integrated with the host cell genome. As the viral DNA is
incomplete or ‘defective’, no infectious virus is produced. However, under its influence, the host
cell undergoes malignant transformation.
A virus-transformed cancer cell is in many ways analogous to a bacterium lysogenised by a
defective phage. In both cases, there is no cell destruction and no virus produced.
Acquisition of new characteristics by the transformed cell resembles lysogenic conversion in
bacteria.
Human papillomavirus (HPV)
Common warts (verruca vulgaris, plantar warts) -types 1,
2, 3 and 4.
Condyloma acumina tumor genital wart, moist, soft,
pedunculated wart found on the external genitalia-types 6
ONCOGE and 11, 42–44. Transmitted venereally and may turn
malignant.
NIC DNA Intraepithelial neoplasia caused by HPV types 6 &11.
VIRUSES Cervical cancer -HPV types 16 and 18.
Laryngeal and oesophageal carcinomas caused by HPV
types 16, 18, 30-33, 51–53.
Prevents new HPV infection but does not treat existing infection or disease. Three recombinant vaccines are now
available:
◦ Quadrivalent vaccine with antigens from HPV 6, 11, 16, and 18.
◦ Nine valent vaccine (HPV 6, 11, 16, 18, 31, 33, 45, 52, 58).
◦ Bivalent vaccine (HPV 16, 18)
Both vaccines are indicated in preventing persistent and precancerous genital lesions in adolescent and young
adult women. They are contraindicated in pregnancy. The WHO recommends 1 or 2 doses for women aged <20
years and two doses, six months apart, for older women.
HPV vaccines available in India are:
i. Quadrivalent vaccines—Gardasil and Cervavac, which is indigenously developed in India
ii. Gardasil-9
HPV vaccine
Human Polyomaviruses
JC virus
Isolated in 1971 from the brain of a patient with Hodgkin’s disease and PML.
Grows only in human fetal glial cell cultures.
Oncogenic, producing malignant gliomas following intracerebral inoculation in newborn.
hamsters.
BK virus
Isolated in 1971 from the urine of a patient who had undergone a kidney transplant.
Can grow in a wide range of primary and continuous cell cultures
Other oncogenic DNA virus
Herpes viruses
Marek’s disease: Fatal contagious neurolymphomatosis of chickens. This is the first instance of
a malignant disease being controlled by a viral vaccine (live attenuated).
Lucke’s tumour of frogs: Renal adenocarcinoma in frogs.
Herpes virus saimiri: Fatal lymphoma or reticulum cell sarcoma when injected into owls,
monkeys or rabbits.
Epstein–Barr virus (EBV): Burkitt’s lymphoma, nasopharyngeal carcinoma.
Other DNA virus
Simian virus 40 (SV40): Transformation is induced in cultured cells
from several species, including human cells. Although no direct
evidence is available, SV40 has been found to be associated with
multiple tumours.
Poxvirus: Three members of the poxvirus group induce benign
tumours—rabbit fibroma, molluscum contagiosum and Yaba virus.
Similar tumours can be induced experimentally in many species of
primates including human beings. The tumours regress
spontaneously in a few weeks.
Adenoviruses: Some types (12, 19, 21) may produce sarcomas in
newborn rodents after experimental inoculation, these viruses do
not appear to have any association with human cancer.
Herpes Viruses
Epstein–Barr virus (EBV)
Found in cultured lymphocytes from Burkitt’s lymphoma patients.
The virus multiplies only in human lymphoid cell lines. Infection is usually asymptomatic.
In young adults without pre-existing antibodies, EB virus infection induces infectious
mononucleosis.
Lymphoma is believed to occur when the infection takes place in children whose immune
systems are compromised.
EB virus-associated lymphomas have been reported in transplant recipients.
EBV has also been linked to nasopharyngeal carcinoma in the Chinese male population in
southeast Asia and East Africa.
Herpes simplex
virus
An association has been proposed (though not proved)
between herpes simplex type 2 infection and cancer of the
uterine cervix.
It has also been suggested that herpes simplex type 1
infection may be associated with cancer of the lip.
Herpes virus type 8 has been linked to Kaposi’s sarcoma.
Cytomegalovirus: It has been associated with carcinoma of the prostate and Kaposi’s sarcoma.
Hepatitis B and C Viruses: Both HBV and HCV are implicated in the causation of hepatocellular
carcinoma.
ONCOGENIC RNA VIRUSES:
Retroviruses
Enveloped, spherical 100 nm viruses released by budding through the host cell
membrane.
Genome has two identical, linear, single-stranded RNA molecules.
The icosahedral nucleocapsid core encloses the helical ribonucleoprotein and
is surrounded by an envelope composed of glycoprotein and lipid.
Have RNA-dependent DNA polymerase or reverse transcriptase
Avian leukosis complex: Antigenically related viruses which
induce avian leukosis (lymphomatosis, myeloblastosis and
erythroblastosis viruses) or sarcoma in fowls (Rous sarcoma virus
[RSV]).
Types Murine leukosis viruses: Several strains of murine leukemia
and sarcoma viruses.
based on Mammary tumour virus of mice: Occurs in certain strains of
mice that have a high natural incidence of breast cancer.
host Leukosis–sarcoma viruses of other animals such as cats,
range
hamsters, rats, guinea pigs and monkeys.
Human T cell leukemia (lymphotropic) viruses (HTLV): HTLV-I-
adult T cell leukemia, tropical spastic paraparesis, a
demyelinating disease. Virus preferentially infects T4 (CD4) cells.
Infected T cells express large quantities of interleukin-2
receptors. HTLV-II:T cell malignancy.
Types based on
host specificity
Retroviruses usually infect only one host species, the
specificity being conditioned mainly by the presence of viral
receptors on the host cell surface.
Depending on their ability to grow in cells from different
species, retroviruses have been classified as following:
◦ Ecotropic (multiplying in cells of native host species only)
◦ Amphotropic (multiplying in cells of native and foreign species)
◦ Xenotropic (multiplying only in cells of foreign species but not of
native host species)
Types based on mode of
virus transmission
Two types of retrovirus transmission occur:
1) Exogenous retroviruses spread horizontally.
2) Endogenous retroviruses are transmitted vertically through a provirus, which is integrated
with the germline cell genome.
The endogenous retrovirus provirus behaves like a cellular gene and is subject to regulatory
control by the host cell.
Endogenous retroviruses are usually silent and do not transform cells or cause any disease.
They can be detected either by ‘activation’ after exposure to radiation or chemicals or by nucleic
acid hybridisation techniques.
Genomic structure
The gag gene codes for the nucleocapsid
core proteins, which are group-specific
antigens (hence the name).
The pol gene encodes the RNA-dependent
DNA polymerase.
The env gene encodes the envelope
glycoproteins.
They may get introduced into the cellular genome a new transforming
gene (oncogene).
Mechanism
of They may induce or alter the expression of a pre-existing cellular
oncogenesi gene.
s
The genes may get overexpressed, and the overproduced gene
product may lead to abnormal growth. Recombination between
retroviral and cellular genes, promoter insertion, chromosomal
translocation, gene amplification, and mutation are some of the
genetic processes relevant in this connection.
Future applications
Identification of virus association with oncogenesis has revolutionised therapeutic and
preventive strategies in some malignancies, e.g., vaccine therapy for human papillomavirus.
The study of viral oncogenesis has helped to understand the process of oncogenesis and
tumour formation in several malignancies.
It has opened up the gates for further research on anticancer drugs and vaccines.
