Unit 4: Virology
211
Lecture 17 - Human cancer viruses
Viruses are etiologic factors in the development of several
types of human tumors, including two great significance
worldwide – cervical and liver cancers.
At least 15-20% of all human tumors worldwide have a
viral cause. The viruses that have been strongly associated
with human viruses include EBV,HCV,HBV,HHV8,and
two retroviral viruses.
Types of tumor viruses
Tumor viruses are of different type: either DNA or RNA
viruses.
DNA tumor viruses encode viral oncoproteins that are
important for viral replication but also affect cellular
growth control pathways.
Most RNA tumor viruses belong to the retrovirus family
which carry an RNA –directed polymerase (reverse
transcriptase) that constructs a DNA copy of the RNA
genome of the virus. The DNA copy becomes integrated
into the DNA of the infected host cell and it is from this
integrated DNA copy that all proteins of the virus are
translated.
RNA tumor viruses are of two general types with respect
to tumor induction:
The highly oncogenic (direct transforming) viruses
carry an oncogene of cellular origin.
The weakly oncogenic viruses don’t contain an
oncogene and induce leukemias after long incubation
periods by indirect mechanism. The two retroviruses
and HCV act indirectly in cancer induction.
Interactions of tumor viruses with their host
a) Persistent infection.
The known tumor viruses establish long term persistent
infections in humans. The chronicity of infection presents
the long term opportunity for a rare event to occur that
allows survival of a cell with growth control mechanisms
that are virus-modified.
b) Host immune responses.
Viruses that establish persistent infections must avoid
detection and recognition by immune system that would
eliminate infection. EBV will restrict expression of viral
genes that makes infected cells nearly invisible to the
host. HPV infect site that are relatively inaccessible to
immune response ( epidermis) HIV cause a mutation in its
antigen that allows escape from antibody and T-cell
recognition, and also causing infection and suppression of
essential immune cells. CMV and adenoviruses cause
modulation of MHC I molecules in infected cells. EBV
causes inhibition of antigen processing.
c) Mechanism of action by human cancer viruses.
There are two general pattern by which tumor viruses
mediate changes in cell behavior. Direct action by
introduction of a new transforming gene into the cell.
Indirect action by altering the expression of a preexisting
cellular gene or genes.
In either case, the cell loses control of normal regulation
of growth process.
d) Cell susceptibility to viral infections & transformation.
Host cells are either permissive or non-permissive for
replication of a given virus.
In DNA viruses, permissive cells are often killed by virus
replication and not transformed unless the viral replicative
cycle that results in death of host cells is blocked in some
way. However, there are situations in which DNA virus
replication doesn’t lyse the host cell and such cells may
be transformed.
RNA viruses are not lethal for cells in which they replicate.
e) Retention of tumor virus nucleic acid in a host cell
The stable genetic change from normal to neoplastic cell
generally require the retention of viral genes in the cell.
With DNA virus, a portion of the DNA of the viral
genome may become integrated into the host cell
chromosome. Sometimes, episomal copies of the viral
genome are maintained in tumor cells. With retroviruses,
the proviral DNA copy of the viral RNA is integrated in
the host cell DNA. Genome RNA copies of hepatitis C
that are not integrated are maintained in tumor cells.
In some cases, viral transformed cells may release growth
factors that affect the phenotype of neighboring
uninfected cells, thereby contributing to tumor formation.
1- Cellular oncogenes
Oncogene is the general term given to genes that are
involved in cancer causation. Normal version of these
transforming genes are present in normal cells and have
been designated proto-oncogen.
Cellular oncogenes are partly responsible for molecular
basis of human cancer. They represent individual
components of complicated pathways responsible for
regulating cell proliferation, division, and differentiation
and for maintaining the integrity of the genome. Incorrect
expression of any component might interrupt that
regulation, resulting in uncontrolled growth of cells.
Unit 4: Virology
211
Two different mechanisms: overexpression and mutation
in proto-oncogene able to convert into oncogene capable
of transforming a cell.
2- Tumor suppressor genes
These are the negative regulators of cell growth. The
inactivation or functional loss of both alleles of such a
gene is required for tumor formation. The example of
tumor suppressor genes are Rb gene by which Rb protein
inhibits entry of cells into S phase by binding to key
transcription factors that regulate expression of S phase
genes.
Another tumor suppressor genes is p35 gene. It also
blocks cell cycle progression; P35 acts as a transcription
factor and regulates the synthesis of a protein that inhibits
the function of certain cell cycle kinases. It also causes
cells with DNA damage to undergo apoptosis.
Human retroviruses
a) Human T-Lymphotropic Viruses (HTLV)
HTLV-1 has been established as the causative agent of
adult T-cell leukemia- lymphoma (ATL) and tropical
spastic paraparesis.
It doesn’t carry an oncogene
Transactivating regulatory genes are believed to be
necessary for viral replication in vivo and may contribute
to oncogenesis by also modulating cellular genes that
regulate cell growth.
b) HIV
The HIV are cytolytic and non-transforming. However,
AIDS patients are at elevated risk of several types of
cancer because of the immune suppression associated
with HIV infection.
Herpesviruses
EBV is etiologically linked to Burkitt lymphoma,
nasopharyngeal carcinoma, popsttransplant lymphomas,
and Hodgkin disease.
EBV encodes a viral oncogene protein (LMP1) that
mimics the activated growth factor receptor.
Several EBV-encoded nuclear antigens are necessary for
immortalization of B cells.
HHV8 is associated with Kaposi sarcoma.
Adenoviruses
They can transform rodent cells but there is no association
with human neoplasia.
HBV and HCV
HBV is a risk factor for causing a liver cancer. It has been
shown that persistent viral infection leads to necrosis,
inflammation, and liver regeneration that over tome
results in cirrhosis. The hepatitis B virus treansactivator
protein , X protein, is a potential viral oncoprotein.
Chronic infection with hepatitis C virus is also considered
to be a causative factor in hepatocellular carcinoma.
How to prove that a virus causes human cancer
1) The geographical distribution of viral infection should
coincide with that of the tumor.
2) The presence of viral markers should be higher in cases
than in controls.
3) The viral infection should precede the tumor.