MI8.

3- Describe the role of

oncogenic viruses in the
evolution of virus associated
malignancy
2148-Harshika Verma
Viruses in Human Cancer

Viruses account for 15% of all

human malignancies
Oncogenes
Oncogenes encode certain proteins (oncoproteins) that trigger the transformation of normal cells
into cancer cells.
™ V-onc (viral oncogenes):
#present in the viral genome are called as viral oncogenes (V-onc).
#essential for the replication of the virus.
#expressed only by certain retroviruses (called as acutely transforming retroviruses)

™ C-onc (cellular oncogenes): They are the cellular counter part of viral oncogenes present in the
cancer cells

™ Proto-oncogenes: They are the cellular counter part of viral oncogenes present in the normal host
cells.
Genes Regulating Host Cell Growth
1. Proto-oncogenes: #promote the host cell growth and proliferation.
#over activation of proto-oncogenes may lead to transformation of the host cells

2. Anti-oncogenes or tumor suppressor genes: #suppress any abnormal proliferation of cells. #Inactivation
of tumor suppressor genes results in cell transformation

3. Apoptosis-regulatory genes:
#They control the programmed cell death by either upregulating or downregulating apoptosis depending on
the requirement.
# Mutations in apoptosis-regulatory genes are another mechanism by which the cellular transformation is
accelerated
4. DNA repair genes:
#Failure of DNA repair genes lead to inability to repair the damaged DNA and may lead to persistent mutation.
Viral Oncogenesis
Establishing persistent infection:
Prolonged interaction between the tumor virus and the host cell is essential for oncogenesis to develop.
Evades host immune response:The oncogenic virus follows various evasion mechanisms to bypass
the host immune response, which are as follows:
„ By restricting the expression of viral genes which go unnoticed by the immune cells [e.g. Epstein-Barr
virus (EBV) in B cells]
„ Infecting the sites that are relatively inaccessible to immune responses [e.g. human papillomavirus
(HPV) infecting epidermis]
„ Undergoing mutation of certain genes that allows the virus to escape from the host cellular and
humoral responses (e.g. HIV)
„ Infection and suppression of essential immune cells (e.g. CD4 T cell by HIV).
Viral Oncogenesis
Immunosuppression of the host allows the cancer cells to proliferate and escape
the host immune response.

Host cell susceptibility:

„ Permissive cells support viral growth and replication of a progeny virus; non-
permissive cells do not
„ Non-permissive cells refer to the host cells that either do not have surface
receptors for viral attachment or do not support the viral replication or the release
of virus progeny
Retention of viral nucleic acid inside the host cells is essential to maintain a
stable genetic change that occurs in a tumor cell
„ The DNA copies of DNA tumor viruses are integrated within the host cell
chromosome
„ RNA of retroviruses gets reverse transcribed into DNA
„ Hepatitis C virus is an exception, its RNA is neither reverse transcribed, nor
integrated into the host chromosome; but are maintained in the tumor cells.
Oncogenic Retroviruses
Acutely-transforming viruses: Slow transforming viruses:
HIV and HTLV-1
They possess viral oncogenes (V.onc) in their
RNA which after being integrated with the host „ They possess additional regulatory gene (e.g.
chromosome, are directly capable of inducing tax gene for HTLV-1and tat gene for HIV) which
oncogenesis after inserting into host chromosome, activates
the host cell machineries that subsequently
„ They are highly oncogenic and cause induces oncogenesis
malignancy within weeks to months
„ They are of low oncogenic potential,
„ Examples- animal retroviruses such as require a long latent period to develop
Rous sarcoma virus. They do not infect man. malignancy
Human T-Cell Lymphotropic Viruses
HTLV-I is a potential human oncogenic virus; associated with several malignancies—
(1) Adult T cell leukemia/lymphoma, (2) cutaneous T cell lymphoma, and (3)
tropical spastic paraparesis.
™Transmission: Occurs through various routes—
(1) from mother to child especially via breast milk (most common) (2) sexual(men to
women), (3) infected blood
™ Target cells: Like HIV, HTLV-I also infects CD4 T cells. GLUT1 (glucose transporter
protein-1) on CD4 T cells acts as receptor for virus attachment
™ Mechanisms of oncogenesis: HTLV-I expresses a unique gene called Tax gene
which has oncogenic potential
Tax
‰ Promotes cell growth cycle: Tax protein inactivates the cell cycle
inhibitor p16/INK4a and activates cyclin D (a cell cycle enhancer), thus
promoting the host cell growth cycle

‰ Tax gene activates nuclear factor κβ (NF-κβ), a transcription factor

that regulates certain host antiapoptoticgenes

‰ Tax gene also interferes with DNA-repair pathways which leads to

sustained DNA mutation.

™ HTLV-I is endemic in certain parts of Japan (10% prevalence) and the Caribbean, but also found
sporadically elsewhere.
AIDS associated malignancies
1.AIDS-defining cancers: These cancers have been enlisted in WHO clinical staging of HIV/AIDS which
include:
„ Non-Hodgkin’s lymphomas (NHLs): It remains the most common cancer in patients with HIV worldwide.

Common NHLs include:

 Burkitt’s lymphoma (associated with EBV)
 Diffuse large B cell lymphoma– often involving the
CNS
 Primary effusion lymphoma (associated with HHV-8)
„ Kaposi’s sarcoma—in association with HHV-8
„ Invasive cervical carcinoma—in association with HPV
Mechanism Of Oncogenesis
There are several pathogenetic mechanisms that contribute to AIDS associated
malignancies.
™ Altered cytokine expression
™ B cell stimulation
™ Associated infections such as HPV, EBV, HHV-8 Genetic alteration
™ Tat protein, an early nonstructural protein of HIV, necessary for virus replication,
has also been linked to the pathogenesis of malignancies
 Hepatitis C Virus associated malignancy
Hepatitis C virus is the only oncogenic virus that does not get integrated with
host chromosome but its RNA remains in the host cell.

™ Similar to HBV, chronic liver cell injury and compensatory regeneration seems to
be the main mechanism
™ In addition, components of the HCV genome, such as the HCV core protein,
may activate a number of growth promoting signal transduction pathways.
Oncogenic DNA Viruses
Ebstein Barr Virus associated malignancies-
Burkitt’s lymphoma (tumor of the jaw seen in children and young adults): EBV is associated with 90% of
African and 20% of non-African cases of Burkitt’s lymphoma
„ Most of the cases have pre-existing mutation [t(8;14)]

™ Nasopharyngeal carcinoma: It is seen among. Chinese people who have history of intake of salted fish
(nitrosamine) and herbal snuff (phorbol ester)
™ Hodgkin’s lymphoma (especially the mixed-cellularity type): EBV DNA is found in Reed-Sternberg cells, in
at least 50% of cases of Hodgkin’s lymphoma
™ NHL (Non-Hodgkin’s lymphoma): All CNS Non Hodgkin’s lymphomas and 50% of systemic nonHodgkin’s
lymphomas are EBV DNA or antibody positive
Mechanism of Oncogenesis
™ latently infected B cells with EBV become immortalized and acquire the ability to grow indefinitely in cell lines
™ Persistent EBV infection can induce malignant transformation of infected B cells and epithelial cells by
expressing latent EBV antigens such as latent membrane protein (LMP) and EBNA (EBV nuclear antigen)

™ Latent membrane protein-1 (LMP-1) i-

„ It is coated on the surface of the infected cells and behaves as active CD40 receptor, a key recipient of helper T
cell signals that stimulate B cell growth
„ LMP-1 also activates the NF- κβ and JAK/STAT signalling pathways and promotes B cell survival and
proliferation
„ LMP-1 prevents apoptosis by activating antiapoptoticfactor BCL2
„ It induces the expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF)
which may contribute to the oncogenesis of nasopharyngeal carcinoma
Human Herpes Virus 8 associated Malignancies
Human Herpesvirus 8 (HHV-8) was first discovered in 1994 in patients with
Kaposi’s sarcoma, hence also called Kaposi’s sarcoma-associated herpesvirus
(KSHV).
™ Epidemiology:
„ In high prevalence area: HHV-8 is endemic in #Africa, where it is transmitted
by oral secretion
„ In low prevalence areas such as #North America, #Asia, #northern Europe, it
affects adults and it is transmitted by sexual route (homosexual men)
Disease Association
Kaposi’s sarcoma -

A soft tissue sarcoma of vascular origin; characterized by red to purple color growth under the skin, mouth, oral mucosa,
lymph nodes, or in other organs.

Primary effusion lymphoma (body cavity-based lymphomas).

Mechanism of Oncogenesis of HHV-8

HHV8 usually infects the endothelial cells and/or hematopoietic progenitor cells.

™ The transformation of malignant cells is directly related to the expression of early lytic genes of HHV-8 such as viral G
protein-coupled receptor K1, viral interleukin-6 (vIL-6) and K15
Human Pappiloma Virus
#They have selective tropism for epithelium of skin and mucous membranes.

Morphology

Papillomaviruses are-
-non-enveloped,
-measure 50–55 nm in size,
-have icosahedral capsids and contain a circular dsDNA.
Viral Genome

Viral genome consists of an early (E) region, a late (L) region, and a noncoding regulatory
region.

™ Early region genes (E1-E7): They code for early nonstructural proteins. The E1 and E2
proteins modulate viral DNA replication.

Products of early genes E6 and E7 have oncogenic potential, by following ways:

„ E6 protein facilitates the degradation of the p53 tumor-suppressor protein

„ E7 protein binds to the retinoblastoma gene product and related proteins.

™ Late region genes (L1 and L2): They code for structural proteins such as capsid
Mechanism Of Oncogenesis
Co-transfection with v-fos DNA results in full
malignant transformation.

There are several other factors that also have been

implicated in the pathogenesis of HPV-induced
malignancies such as:

™ Presence of other genetic co-factors like mutated

RAS

gene

™ Cigarette smoking

™ Coexisting microbial infections

™ Dietary deficiencies

™ Hormonal changes.
 HBV Active Prophylaxis

Hepatitis B vaccine is a recombinant subunit vaccine.

™ The surface antigen (HBsAg) is used as vaccine candidate which is prepared in Baker’s yeast by DNA recombinant technology by cloning the S
gene into the yeast chromosome

™ Route of administration: Vaccine is administered by intramuscular route over deltoid region (in infant anterolateral thigh)

™ Dosage: 10–20 µg/dose (half of the dose is given to children below 10 years)

™ Schedule:

„ Recommended schedule for adults: Three doses are given at 0, 1 and 6 months

„ Under national immunization schedule: It is given at 6, 10, 14 weeks (along with DPT vaccine). Additional dose at birth may be given in areas
with prevalence of HBV more than 8%

„ Minimum interval between the doses—4 weeks

„ If
there is documentaion of partial vaccination (1 or 2 doses): Then do not restart; just complete the
vaccine series, regardless of when the last dose was taken.

™ Marker of protection: Recipients are said to be protected if they develop seroconversion with an anti-
HBsAg antibody titer of ≥ 10 mIU/mL

„ Seroconversion occurs in about 95% of infants, children and young adults. However, among older
people (>60 years), the protection is about 65–75%
Re-vaccination: If titer remain <10 mIU/mL after first series of vaccination; the HCW
is subjected to second series of vaccination (3 doses at 0, 1, 6 months)

™ Non/low responders: About 5–10% of individuals do not show seroconversion

even after two series of vaccination; i.e., six doses of vaccination. They are called as
non-responders. They do not need any further vaccination
Hepatitis B Virus Associated Malignancy
Hepatitis B virus (HBV), in adjunction with hepatitis C is responsible for 70–85% of
hepatocellular carcinomas worldwide.

Mechanism of Oncogenesis-

Immunologically mediated chronic inflammation- Most DOMINANT

mechanism
Immunologically Mediated Chronic Inflammation
In chronic viral infection,
hepatocellular injury occurs—> compensated by proliferation of hepatocytes—>
regenerative process(growth factors, cytokines, chemokines, and other bioactive
substances are produced by the activated immune cells)---> promote cell survival,
tissue remodeling and angiogenesis

„ The activated immune cells also produce reactive oxygen species, that are
genotoxic and mutagenic

„ One key molecular step seems to be activation of the NF-κβ pathway in

hepatocytes which in turn blocks apoptosis, allowing the dividing hepatocytes to
incur genotoxic stress and to accumulate mutations.
 Other Mechanisms

#Hepatitis B X gene (HBx), a regulatory gene in HBV genome, can activate the
transcription of cellular and viral genes.

#Deletion of tumor suppressor genes

: Integration of viral DNA with the host genome can cause secondary rearrangements
of chromosomes which may lead to deletion of tumor suppressor genes.