Date: Mon, 6 Feb 1995 12:34:37 +0500
From: awilson@smtpinet.aspensys.com (Wilson, Anne)
Subject: NIAID News: Host Factors Key to Control HIV

N E W S   R E L E A S E
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National Institutes of Health
National Institute of Allergies and Infectious Diseases
January 30, 1995


      Fauci:  Host Factors Key to Control of HIV Infection
 
      The body has potent mechanisms for containing HIV, including
immune system cells called CD8+ T cells, that may be more effective
than any antiretroviral drug in controlling HIV infection, says Anthony S.
Fauci, M.D., director of the National Institute of Allergy and Infectious
Diseases (NIAID) and chief of the NIAID Laboratory of
Immunoregulation (LIR).  Recent LIR studies of these mechanisms --
generically known as "host factors" -- have provided researchers with
potential new targets for therapeutic intervention.
      Dr. Fauci will discuss "Host Factors in the Pathogenesis of HIV
Disease" and his laboratory's recent findings on Monday, Jan. 30 at
8:30 a.m. at the Second National Conference on Human Retroviruses
and Related Infections at the Sheraton Washington Hotel in
Washington, D.C.  Dr. Fauci also will participate in a press briefing at
11:30 a.m. at the hotel.
       "Recent studies of long-term non-progressors, HIV-infected
individuals who show no decline in immune function for many years,
demonstrate that certain immune responses can be very effective at
containing the replication and spread of HIV," says Dr. Fauci.  "The
effectiveness of such factors is also observed in most other HIV-
infected individuals in the weeks following infection with HIV, when the
virus is contained to a large degree following its initial dissemination. 
Our laboratory has been working to delineate the host factors that slow
the progression of HIV disease, with an eye toward their use as targets
for therapies to augment antiretroviral drugs."
       Dr. Fauci and his colleagues have recently focused on how
cytokines (the signalling molecules of the immune system) and the
interactions between various immune system cells induce the
replication of HIV, and how such replication might be controlled.
      The researchers have found that when dendritic cells, which
present invaders to the immune system for processing, interact with
CD4+ T cells in an HIV-infected individual, HIV replication increases. 
      In laboratory experiments, CD4+ T cells taken from HIV-infected
individuals produced very little HIV, even when interleukin-2 (IL-2), a
cytokine that can stimulate HIV replication, was added.  However, when
the investigators added dendritic cells taken from the same individual,
significant amounts of virus were produced. 
       "The normal cell-to-cell interactions that take place in the
environment of the lymph node, where dendritic cells constantly come
into contact with infected CD4+ T cells, probably result in the
upregulation of HIV expression," says Dr. Fauci.  
      Dr. Fauci and his group also have provided new information on
how CD8+ T cells may suppress virus replication.  When the
investigators cultured CD4+ T cells together with dendritic cells from an
HIV-infected individual, they noted significant HIV replication, but when
they added CD8+ T cells, HIV replication was largely blocked. 
      They also found that CD8+ T cells can block the cytokine
signals that normally influence HIV replication.  In a series of in vitro
experiments, they added cytokines such as tumor necrosis factor,
interleukin-1-beta or interleukin-6 (all of which can boost HIV replication
in infected cells) to mononuclear cells of an HIV-infected individual and
found little or no virus production.  However, when CD8+ T cells were
removed from the cell suspension, the same cytokines induced
significant HIV replication.  When CD8+ T cells were returned to the
cell culture, virus replication was once again suppressed.  
      "Our data suggest CD8+ T cells are able to block both the cell-
to-cell interactions and the cytokine signals that upregulate HIV
expression," Dr. Fauci explains.
       The researchers also have found that adding IL-2 to CD4+ T
cells from HIV-infected individuals caused very little viral replication
when CD8+ T cells were present.  The reason for this, they
demonstrated, is that IL-2 induced the suppressing function of CD8+ T
cells, which overrode the cytokine's other effect of boosting viral
replication in CD4+ T cells.
      "Our studies show that IL-2 is a potent inducer of the
suppressor phenomenon in CD8+ T cells, a function that supersedes its
ability to induce virus production in CD4+ T cells," says Dr. Fauci.
      In contrast, the researchers found that interleukin-12 (IL-12), a
less potent inducer of viral replication in CD4+ T cells, did not
significantly induce suppressing activity in CD8+ T cells, and induced
production of virus to varying degrees.  
      "Taken together, our studies show that cytokines not only
induce HIV expression in a complex manner, but they are also involved
in the modulation of those host factors that control HIV expression,
such as CD8+ T cells," says Dr. Fauci.
      "These studies add to what we have learned from our studies of
long-term non-progressors, a group of individuals who comprise an
extraordinarily useful cohort for studying host factors," he adds.  
      As noted in the Jan. 26, 1995 issue of The New England
Journal of Medicine by Dr. Fauci and others, studies of these
individuals show that most have low-to-moderate levels of CD4+ T cell
activation as well as significant CD8+ T cell suppressor activity.
      "It is likely that long-term non-progressors are a heterogeneous
group: some may be infected with a weakened virus, while others are
examples of how host factors, in some circumstances, can contain HIV
disease," says Dr. Fauci.  "Since we know from studying long-term non-
progressors that the immune system may be more powerful than any
antiretroviral agent in containing the spread of virus over a long period
of time, it makes sense to augment antiretroviral therapy with
modulation of the immune system."
      Toward this end, NIAID researchers have treated a small
number of patients with intravenous infusions of IL-2, given for five
consecutive days every two months over a period of two to three years,
in addition to antiretroviral therapy.  Preliminary results have been
encouraging with significant and sustained rises in CD4+ T cell counts
in the majority of individuals with CD4+ T cell counts greater than
200/mm3 of blood.
      NIAID, a component of the National Institutes of Health,
supports investigators and scientific studies at universities, medical
schools, hospitals and research institutions in the United States and
abroad aimed at preventing, diagnosing and treating such illnesses as
AIDS, tuberculosis and asthma as well as allergies.  NIH is an agency
of the U.S. Public Health Service, part of the U.S. Department of Health
and Human Services.
                           
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