New data show that latent pools of infected cells are established very
early in the course of HIV infection, even if a patient is treated
expeditiously with highly active antiretroviral therapy ("HAART" -
generally a three- or four-drug combination that includes a protease
inhibitor). 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), will present these and other new
findings at the 12th World AIDS Conference in Geneva, Switzerland.
"We have shown that initiating HAART as soon as 10 days after the onset
of the symptoms of acute HIV infection does not prevent the formation of
a latent reservoir of virus," says Dr. Fauci. "By the time high levels
of HIV are detectable in the blood, the virus probably has spread to the
lymphoid organs and established a pool of latently infected cells.
"Our group and others are pursuing studies to identify and treat people
recently exposed to HIV, before the burst of virus replication, which
occurs in most patients soon after infection. Such studies will help
determine whether it will be possible to prevent the early establishment
of latent pools of HIV."
In Geneva, Dr. Fauci also will discuss the potential for diminishing
latent pools of HIV - the possibility of "flushing out" the virus (at
least in the test tube) - by stimulating latently infected CD4+ T cells
with antibodies to the CD3 molecule on the cell surface, or with
combinations of cytokines such as interleukin-2 (IL-2), interleukin-6
(IL-6) and tumor necrosis factor-alpha (TNF-alpha).
"This approach to purging the HIV from latently infected cells assumes
that cells activated to release virus will spontaneously die, and the
released virus will be prevented from spreading to other cells because
of the HAART that the patients are receiving," Dr. Fauci says. "In our
in vitro studies, we have shown that it is indeed possible to decrease
the number of latently infected cells, but a single round of purging
does not completely eliminate the virus.
"Further in vitro studies, as well as clinical trials with HIV-infected
patients, will help determine the feasibility of completely eliminating
the latent reservoir of HIV-infected cells by repeated, intermittent
exposure to activation signals in the setting of HAART," he says.
Dr. Fauci notes that numerous factors are involved in the initiation of
HIV infection, in determining levels of viral replication in people
infected with HIV, and ultimately, in the rate of disease progression
among HIV-infected individuals. Among these are factors intrinsic to
the infected individual (the "host"), notably the network of immune
signalling molecules (especially cytokines and CC-chemokines) involved
in the normal immune response.
"Pro-inflammatory" cytokines such as IL-2, IL-6 and TNF-alpha, boost
replication of certain strains of HIV. CC-chemokines such as RANTES,
MIP-1alpha and MIP1-beta, can have either a positive or negative effect
on HIV replication, depending on the strain of the virus. "The emerging
picture of HIV pathogenesis is one of a 'delicate balance' between
factors that drive viral replication and those that inhibit the virus,"
says Dr. Fauci.
When an HIV-infected patient is taking HAART, pro-inflammatory 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 can reduce viral replication dramatically, sometimes to the point
where HIV can be found only in a latent form within the genes of resting
CD4+ T cells. Dr. Fauci and colleagues have shown in vitro that when
HAART is withdrawn, the effects of HIV-inducing cytokines and other
factors once again promote the active production of virus.
"We feel that these data provide a mechanistic explanation for the
clinical phenomenon of rapid viral 'rebound' in many patients with low
or undetectable levels of virus in their bloodstream who discontinue
HAART. When a patient stops taking HAART because of toxicity or other
reasons, or if HIV becomes resistant to the drugs, the virus almost
inevitably comes roaring back because latently infected cells are awash
in stimulatory factors in the normal environment of the lymph nodes,"
says Dr. Fauci.
"These data underscore the need to develop comprehensive treatment
strategies that not only block HIV replication but also modulate the
host factors that drive such replication."
The lead investigators in the NIAID studies to be discussed are Drs.
Fauci and Tae-Wook Chun of the LIR. Collaborators include Delphine
Engel of the LIR, and Drs. Lawrence Corey and M. Michelle Berrey, and
Theresa Shea of the University of Washington in Seattle.
NIAID is a component of the National Institutes of Health (NIH). NIAID
conducts and supports research to prevent, diagnose and treat illnesses
such as HIV disease and other sexually transmitted diseases,
tuberculosis, malaria, asthma and allergies. NIH is an agency of the
U.S. Department of Health and Human Services.