"Latently infected, resting CD4+ cells, although relatively few in
number, may be the embers that re-ignite active HIV infection if a
patient stops taking combination therapy, or if the drugs become
ineffective," says the paper's lead author, Tae-Wook Chun, Ph.D., of the
NIAID Laboratory of Immunoregulation (LIR). "Our new data suggest that
the virus rapidly rebounds because of factors present in the normal
environment of the lymph nodes, particularly cytokines, which stimulate
these cells to produce virus."
HAART (potent combinations of HIV drugs, generally including a protease
inhibitor) can reduce the amount of virus in a person's plasma to levels
that are not detectable by the most sophisticated laboratory tests.
Despite the powerful effects of these drugs, however, HIV is not
completely eliminated from the bodies of persons taking them. Rather,
the virus persists in safe havens where the immune system cannot detect
it. These hiding places include non-dividing, resting CD4+ T cells in
the blood and lymph nodes, which can harbor HIV DNA for prolonged
periods while remaining invisible to the immune system. In an
HIV-infected person's body, 1 to 10 of every million resting CD4+ T
cells contain HIV that is capable of replicating.
Many scientists think that these viral sanctuaries pose the greatest
challenge to the long-term control of HIV infection in patients
receiving anti-HIV therapy.
The new data from the LIR buttress this view. In a series of in vitro
experiments, Dr. Chun and his colleagues found that resting, latently
infected CD4+ cells readily produced virus when bathed in stimulatory
molecules found in the normal environment of the lymph node. If the
drugs that comprise HAART were added to the cells, no virus was
"Without HAART, we found that interleukin-6, tumor necrosis factor-alpha
and interleukin-2, signalling molecules which are normally found in
copious amounts in a person's lymph nodes, readily induced HIV
replication in latently infected, resting CD4+ T cells," says Dr. Chun.
"Our in vitro findings help explain the well-documented phenomenon of
viral rebound seen in virtually all patients with no easily detectable
virus in their blood as a result of HAART who discontinue therapy."
The researchers found that the cytokine combination activated purified
resting CD4+ T cells from both HIV-infected patients receiving HAART,
and from HIV-infected patients who had never taken HAART. Previous
studies had shown that the three cytokines could independently induce
HIV replication in cell lines, and in certain cells from the
bloodstream. Before this study, however, the effects of the cytokines
on latently infected, resting CD4+ T cells were unclear.
The new data suggest possible approaches to "purging" the body of cells
latently infected with HIV.
"We now know that it is possible to drive latently infected CD4+ cells,
at least in vitro, to a state of productive infection by using
combinations of cytokines and/or antibodies to the CD3 molecule on the
cell surface," says Anthony S. Fauci, M.D., NIAID director, LIR chief
and senior author on the paper. "Thus, one approach to purging these
cells might be to stimulate them to spit out virus under the cover of
HAART. Two assumptions are built into this scenario: cells activated to
produce virus will die, and HAART will prevent the spread of released
"Our group and others are pursuing further laboratory studies as well as
clinical trials with HIV-infected patients to determine if such an
approach is feasible."
Co-authors of Drs. Fauci and Chun include Delphine Engel, Stephanie B.
Mizell and Linda Ehler.
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.