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Discussion -- Pathogenetic Factors
A number of pathogenetic factors have been either
implicated or proposed for classic and AIDS-associated
KS, including various viral agents. The most common viral
agents identified within KS lesions are from the herpes
virus family.
In the last several years, a unique herpesvirus-like DNA
sequence has been identified by representational
difference analysis in KS. KS330 and KS631 bands are
specific to KS and their protein products have homology
with herpesviral polypeptides. KS330 has homology with
other known gamma herpesvirus members. KS330 is a 233
base pair DNA sequence which has homology with ORF26 from
herpes saimiri, which causes fulminant lymphoma in new
world monkeys. This DNA sequence also has homology with
BDLF1 ORF from another gamma herpes virus, EBV. Although
there is a remarkable DNA sequence homology among these
DNA sequences, the cloned polypeptide is not homologous
for the proteins encoded by herpes saimiri and EBV, and
provides evidence that a related, but distinct gamma
herpesvirus has been identified. This new member of the
gamma herpesvirus family has been designated, HHV-8 or
KSHV. Additional cloned proteins from HHV-8 DNA
correspond to the major capsid proteins from herpes
saimiri and EBV proteins.
Detection of KS330 can be carried out by PCR
amplification following DNA extraction from
paraffin-embedded, formalin-fixed tissue sections. PCR
detection of KSHV/HHV-8 is performed using a 233 base
pair amplicon with 51% G:C composition. KS330 has been
detected in 53 of 54 oral AIDS-KS lesions evaluated
(Figure 9).
KSHV/HHV-8 has been identified in a high proportion of
all forms of Kaposi’s sarcoma, including classic KS.
It would appear as though this gamma herpes virus may be
transmitted by a number of routes. It has been detected
in serum, peripheral blood mononuclear cells, bronchial
fluid, semen and saliva in individuals with KS. It has
also been detected in some HIV positive individuals who
do not have clinical lesions; however, it predicts the
occurrence of KS in such individuals. KSHV/HHV-8 has been
identified by PCR-in situ hybridization in both
endothelial cells and spindled stromal cells forming KS
lesions.
KSHV/HHV-8 is an infectious agent transmitted independent
of HIV and has been identified in men, women and children
with KS lesions either in the presence or absence of HIV
infection. Detection of KSHV in peripheral blood
mononuclear cells correlates with the presence of AIDS-KS
and in the asymptomatic HIV-infected patient predicts the
development of KS. Although KSHV/HHV-8 is integrated into
the DNA of KS lesions, only 1 copy number per cell is
present. The presence of this viral agent may influence
expression of proliferative factors such as cytokines and
HIV-1 tat protein without transforming the cells.
KSHV/HHV-8 has also been identified in the unique body
cavity B-Cell lymphomas seen in AIDS. 40 to 60 copies per
cell of KSHV/HHV-8 have been shown to be integrated into
the DNA of these neoplasms. KSHV/HHV-8 is a gamma herpes
virus along with EBV.
KSHV/HHV-8 plays a role in the proliferative process
similar to that of EBV in lymphoproliferative disease.
This virus has been implicated in body cavity lymphomas
in HIV/AIDS and in Castleman’s disease. The
particular DNA sequence, KS330, HHV-8 appears to be
highly conserved with only three genomic differences in
patients with both AIDS and non-AIDS associated KS. This
genomic variation is within expected limits for viral
strain variation. Previously, the virus could only be
detected by molecular techniques. In March 1996, the
ability to grow and propagate KSHV/HHV-8 in cell cultures
has been reported. Confirmation of this virus within cell
cultures was determined by molecular techniques and in
addition, the ultrastructural appearance of this virus
was also demonstrated and it has also been demonstrated
in the present case. More recently, the transforming
ability of KSHV/HHV-8 has been confirmed. A
G-protein-coupled receptor (ORF74) encoded by HHV-8 has
been shown to be a viral oncogene and signals cell
proliferation in a constitutive manner. Cellular
signalling by this KSHV G-protein-coupled receptor leads
to transformation, and tumor formation by inducing
angiogenesis via vascular endothelial grow factor and
activates two protein kinases (JNK/SAPK and p38MAPK)
which are angiogenic activators and mitogens for both
Kaposi's sarcoma cells and B lymphocytes.
Treatment of Kaposi’s sarcoma may either be local or
systemic depending upon the extent of involvement and the
patients symptoms. Systemic therapy has been performed
with a variety of agents. Local therapy has varied from
excision of lesions, laser fulguration to intralesional
administration of chemotherapeutic agents and sclerosing
agents. The ability to grow KSHV/HHV-8 in cell cultures
opens up new avenues of therapy. It is possible in the
not to distance future to envision the development of an
anti-viral agent against KSHV/HHV-8 as a treatment
modality. Development of a vaccine against KSHV/HHV-8 may
also be on the horizon as well.
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