Data Suggest Strategies to Purge Latently Infected Cells
"Our new data suggest that the virus comes roaring back
because of the normal stimulatory factors present in the environment
of a patient's lymph nodes, notably signalling molecules called
cytokines," says Anthony S. Fauci, NIAID Director and Chief of the
NIAID Laboratory of Immunoregulation (LIR). "In the absence of
antiretroviral therapy, these factors activate HIV that is hiding in a
latent form in immune system cells."
In a series of in vitro experiments, the NIAID researchers
found that inductive factors can activate reservoirs of latent HIV in
resting CD4+ T cells, if potent combinations of antiretroviral drugs are
not present. Such drug combinations, which generally include a
protease inhibitor and two or three other drugs, are commonly
referred to as "highly active antiretroviral therapy" or HAART.
Dr. Fauci's team and two other groups recently demonstrated
that reservoirs of latent HIV can be found in resting CD4+ T cells of
patients who have taken HAART for many months (see, for e.g., Chun
et al., PNAS, Nov. 25 1997). Among Dr. Fauci's new findings are
data that suggest that it may prove possible to purge these reservoirs
of latent HIV by activating resting, latently infected CD4+ T cells with
cytokines, resulting in the death of these cells, while preventing
further viral spread with HAART.
Dr. Fauci will present his laboratory's new observations at the
5th Conference on Retroviruses and Opportunistic Infections in
Chicago, Ill., on Wednesday, February 4 at 6:30 p.m. in the Sheraton
Chicago Ballroom. The lecture is part of a special symposium chaired
by Dr. Fauci called "Host Factors in HIV Infection: Implications for
Therapy." The symposium also features Drs. Stephen O'Brien of the
National Cancer Institute, Barton Haynes of the Duke University
School of Medicine, and Giuseppe Pantaleo of Centre Hospitalier
Universitaire Vaudois in Lausanne, Switzerland.
When an HIV-infected patient is taking HAART, inductive
cytokines and other factors which can boost HIV production are still
present in their lymph nodes and related organs. However, the
powerful effects of HAART nonetheless can reduce viral replication
dramatically, sometimes to the point where HIV can be found only in a
latent form in resting CD4+ T cells. The new data suggest that when
HAART is withdrawn, the effects of HIV-inducing cytokines and other
factors once again promote the active production of virus.
"The findings underscore the risks involved in discontinuing
antiretroviral therapy, even if a patient feels better and has a viral
load that is 'undetectable' using standard assays," Dr. Fauci says. "Our
data also stress the importance of developing comprehensive
treatment strategies which not only block HIV replication but also
modulate the host factors that drive such replication.
In studies dating back to the mid-1980s, Dr. Fauci and his
team have shown that certain cytokines normally secreted by immune
cells, particularly in the lymph nodes, can boost the replication of
HIV. Blocking these so called "inductive" cytokines, such as tumor necrosis
factor-alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), and
interleukin-6 (IL-6), can markedly reduce viral replication.
Conversely, as LIR scientists first described in 1987, even resting,
latently infected cells can be induced to actively produce HIV when
cytokines such as TNF-alpha are added. More recent LIR
experiments have shown that other stimuli, such as the activation of
immune system cells by immunization, can also induce latently
infected cells to actively produce HIV. In addition to these factors, a
group of molecules called CC-chemokines, which suppress the
replication of certain strains of HIV, can enhance the replication of
HIV in some circumstances.
"HIV disease is a multifactorial process controlled by the
complicated interplay of stimulatory and inhibitory factors
concentrated in the lymphoid tissue, the centers of immune activity in
the body," Dr. Fauci notes.
At the Chicago symposium, Dr. Fauci will present data from in
vitro experiments involving latently infected CD4+ T cells drawn from
HIV-infected, HAART-treated individuals, as well as from HIV-infected
patients not receiving HAART.
In one series of experiments, the researchers found that after
adding HAART to cultures of latently infected, resting CD4+ T cells,
they were unable to induce with cytokines the production of HIV from
the cells of either group of patients.
"However, when we took HAART out of the cultures, we were
able to rapidly induce HIV replication with cytokines, even in cells
from patients who had been on HAART for many months," says Dr.
In another in vitro experiment, the researchers sought to
determine if they could purge HIV from latently infected CD4+ T cells.
They exposed the cells to the inductive cytokine interleukin-2 (IL-2)
for six days, both with and without HAART added to the cultures.
The researchers reasoned that if they induced latently infected
CD4+ T cells with IL-2 in the absence of HAART, the cells would
make virus and die, but would still infect other cells. Thus, inducing
HIV with a cytokine but without HAART would have a detrimental
effect. In the presence of HAART, the thinking went, cells induced to
make virus would also die, but would be unable to infect new cells
because of the powerful antiviral effects of the drugs. Thus, HAART
together with IL-2 would lead to a depletion of latently infected cells.
In the experiments, the researchers found that latently
infected CD4+ T cells that contained inducible virus and were treated
with both IL-2 and HAART did, indeed, dramatically decline in
"This work provides the rationale to attempt to purge latently
infected CD4+ T cells in HIV-infected patients by using a similar
approach, i.e., by deliberately inducing virus expression in the setting
of HAART," says Dr. Fauci.
NIAID researchers are currently testing this approach in HIV-infected
volunteers receiving IL-2 and antiretroviral drugs at the NIH Clinical
Center in Bethesda, Md.
NIAID, part of the National Institutes of Health (NIH), supports
biomedical research to prevent, diagnose and treat illnesses such as
AIDS, tuberculosis, malaria, asthma and allergies. NIH is an agency
of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are
available via the NIAID home page at http://www.niaid.nih.gov.