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Several new lymphotropic viruses have been identified and new
associations between known viruses and disease have emerged.
There are
two families of viruses that contribute to lymphomagenesis in humans:
herpesviruses and retroviruses. The two herpesviruses are the
Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8). Human T-cell
leukemia virus-1 (HTLV-1) is a retrovirus which is the causative agent
of adult T-cell leukemia/lymphoma (ATL).
Infection with
human immunodeficiency virus (HIV) is also associated with a greatly
increased risk of lymphoma development although here the role of the
virus appears to be indirect.
Visit:AIDS related malignant tumours
Lymphotropic Herpesviruses:
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Epstein-Barr Virus Related Malignant Tumours
EBV was first
identified because of its involvement in
Burkitt’s lymphoma
(BL) and was later shown to be associated with
infectious mononucleosis
and
nasopharyngeal carcinoma.
The virus is
almost invariably found in endemic BL which occurs in areas of malaria
such as equatorial Africa and Papua New Guinea.
It is also
associated with the majority of BL cases in South America but is less
often found in sporadic and AIDS-associated BL .
In EBV-associated
cases, all of the tumour cells are infected by virus and the viral
infection is clonal suggesting that the virus is likely to play a role
in disease pathogenesis.
Viral gene
expression, however, is tightly restricted with only one nuclear
protein, EBNA1, and the small EBER RNA molecules being expressed.
EBV is also
associated with lymphomas occurring in immunosuppressed persons,
notably transplant recipients and AIDS patients.
The
B-cell
lymphoproliferative disease (BLPD) lesions seen in transplant
patients in many ways resemble lymphoblastoid cell lines generated
by infection of peripheral blood in vitro.
Lesions may
regress following reduction or withdrawal of immuno-suppressive
therapy, even at a stage when they appear monoclonal. This suggests
that these tumours are purely virally driven, at least in the early
stage.
In the last
decade EBV has been firmly linked to a proportion of cases of
Hodgkin’s disease.
In EBV-associated
cases the virus is present in all Reed-Sternberg cells, the viral
infection is clonal and EBV gene products are expressed.
In addition to
the EBNA1 protein and EBER RNAs , Reed-Sternberg cells express the
LMP-1 protein which is known to have oncogenic potential in
experimental systems, thus it would appear likely that the virus is
contributing to disease pathogenesis.
In developed
countries EBV-associated cases account for about a third of all cases
.
Mixed cellularity
cases are much more likely to be EBV-positive than nodular sclerosis
cases and paediatric and older adult cases are more likely to be
positive than cases on the young adult age incidence peak.
EBV is also
invariably associated with several other rarer tumors including
pyothorax-associated lymphomas and nasal NK/T-cell lymphomas (lethal
midline granuloma) .
The virus is also
frequently found is association with HHV-8 or Kaposi’s
sarcoma-associated herpes virus (KSHV) is the most recently identified
human herpes virus.
Viral genomes
were first detected in
Kaposi's Sarcoma
(KS) using molecular techniques and it was only later viral particles
were visualized by electron microscopy. HHV-8 is associated with all
forms of KS although whether it is causal remains to be determined.
The virus is also
associated with
primary effusion lymphomas and
multicentric
Castleman’s disease
and here, particularly in the former
condition, a role in the pathogenesis appears more certain.
Recently it has
been suggested HHV-8 may have an indirect role in multiple myeloma
(virus encodes a homologue of the inter-leukin-6 protein).
Retrovirus:
HTLV-1 was the
first human retrovirus to be identified and is causally associated
with adult T-cell leukaemia, an aggressive malignancy of mature
T-cells.
Unlike EBV,
HTLV-1 has a restricted geographical distribution and incidence
follows the occurrence of the virus.
Retroviruses have
much smaller genomes than herpesviruses, however HTLV-1 encodes
several proteins, in addition to the viral structural proteins, which
are believed to be involved in transformation.
The most well
characterized of these is the Tax protein which has the ability to
up-regulate viral and cellular genes including the interleukin-2
receptor gene.
In 1997 the
identification of a fifth human retrovirus (HRV5) was reported. Little
is known about this virus at present as it has not been possible to
grow it in vitro and the virus has only been found at very low levels
in clinical samples. Any association with leukaemia and lymphoma
remains to be determined.
There is now very
clear evidence for an association between several human viruses and a
diverse range of lymphoid diseases. It is likely that with the
availability of more sophisticated techniques additional viruses will
be identified in the future and more disease associations will emerge.
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