BIOLOGY OF HIV AND HHV-6 INTERACTIONS

Acquired Immunodeficiency Syndrome (AIDS) is a severe disease caused by
a human retrovirus, Human Immunodeficiency Virus (HIV). It is generally
believed that all HIV infected individuals will eventually develop AIDS.
However, the time frame from initial infection to the development of
clinical AIDS is extremely variable. Some infected individuals develop
the disease within months of infection while in some may take years. It
is likely that the virus exists for prolonged periods in a latent form
in infected individuals. It has been postulated that various factors
may be involved in triggering the virus into an active state of
replication and thus causing the disease. These factors include
antigenic stimulation or superinfection by other viruses. Recently, a new human herpes virus-6 (HHV-6) was isolated from AIDS
patients, patients with lymphoproliferative disorders and infants with
roseola. Since HHV-6 also infects in vitro the same human target cells
as HIV and produces a productive infection, it will be essential to
study the role played by HHV-6 infection and replication in
HIV-pathogenesis. We have recently demonstrated that HHV-6 can
transactivate HIV-1 LTR in human T cell lines. Our preliminary studies
show that HHV-6 can also transactivate HIV LTR in T lymphoblasts from
norman human peripheral blood. In addition, HHV-6 and HIV-1 have been
shown to productively co-infect individual human CD4+ T lymphocytes,
resulting in accelerated HIV-1 expression and cellular death. It could
be hypothesized that activation of latent HIV-1 by HHV-6 or vice versa,
may generate a vicious cycle resulting in the depletion of CD4+ cells.
HHV-6 may also play a role in the pathogenesis of AIDS by acting through
CD4+ cytolysis or modulation or by chronic antigenic stimulation leading
to suppression of the T cell regulatory mechanisms and may lead to tumor
development and progression. Our overall objective of this proposed
project is to understand how HHV-6 acts as a co-factor in HIV
activation, its mechanisms involved and its significance in activating
latent HIV infection. Our approach is to first identify the HHV-6
gene(s) that is involved in HIV activation. We are also proposing to
see if HIV itself can activate HHV-6 replication, since in vitro, HHV-6
infection alone is cytolytic for T cells. Enhancement of HHV-6
production by HIV in AIDS may also be an important factor in T cell
depletion in AIDS patients. Several HHV-6 isolates with varying in
vitro tropism have been identified and we will examine the ability of
HHV-6 isolates with diverse tropism to activate HIV promoter and HIV in
T cell lines and primary T blast cells. The studies proposed here are significant as they will generate valuable
information in understanding how HHV-6 can act as co-factor in AIDS,
mechanisms involved and especially its role in converting latent HIV
infection.