"These findings are not unexpected," comments Anthony S. Fauci, M.D.,
director of the National Institute of Allergy and Infectious Diseases
(NIAID), which provided major support for both studies. "The data add to
other recent findings indicating that it may be impossible to eradicate HIV
from the body with currently approved antiretroviral therapy. What all
these studies underscore is the pressing need to develop more effective,
less toxic medications that can be used over the long term to suppress HIV,
as well as novel strategies to then purge residual virus from the body and
boost the immune system. In this regard, many important leads are being
pursued by investigators in government, academia and industry."
The era of highly active antiretroviral therapy, or HAART, began about three
years ago when the first protease inhibitors were incorporated into
multi-drug HIV treatment regimens that included older anti-HIV drugs such as
AZT. Hopes that the drugs could "cure" AIDS were raised when some patients
experienced dramatic drops in the level of HIV in their plasma. More
sophisticated studies, however, subsequently turned up evidence that some
virus survived the therapy by hiding in certain cells and tissues.
The NEJM studies were conducted by separate groups of investigators from the
Aaron Diamond AIDS Research Center in New York, led by Linqui Zhang, Ph.D.,
and David Ho, M.D., and from Northwestern University Medical School in
Chicago, led by Manohar Furtado, Ph.D., and Steven Wolinsky, M.D. Both
groups focused attention on the reservoir of HIV found within circulating
blood cells of patients who had successfully suppressed HIV in their plasma
with HAART. The patients were taking various combinations of three to four
anti-HIV drugs, including protease inhibitors. With strict adherence to
HAART, all had kept HIV below detectable levels for approximately two to
Although evidence has been accumulating that HAART may not wipe out all
traces of the virus, it has been unclear what feeds the low-level residual
infection. One unanswered question, for example, was whether HAART
completely stops viral replication. If not, evidence of viral replication
could mean a small but unending source of replicating HIV exists to
replenish the reservoir.
To look for evidence of ongoing viral replication, Dr. Zhang and his
colleagues studied four sequential cell samples taken from each of eight
patients. They examined latently infected cells for changes in the genetic
makeup of HIV from sample to sample, which could indicate ongoing
replication of HIV. The cells from six patients showed few if any such
changes. Over time, however, significant variations in the genetic makeup
of HIV's coat protein appeared in cells taken from the other two patients.
The changes, the researchers note in their paper, are "likely due to ongoing
residual replication, albeit at an exceedingly low level." Studies of
various tissue samples and body fluids from one of the two patients
confirmed residual HIV replication in cells taken from his lymph nodes,
tonsils and gastrointestinal tract.
The Northwestern University group examined at least five sequential blood
samples taken from each of five men who also had used HAART to keep HIV
below measurable levels for 20 months or more. To investigate the
characteristics of the HIV reservoir in these men, they measured changes in
the concentrations of HIV DNA and viral RNA in cells over time. They
observed that after an initial rapid decline, the levels stabilized,
indicating that viral replication persisted. This plateau, they say,
suggests that the rate at which cells become infected with newly made virus
is approximately equal to the rate at which older infected cells die.
"Unless this quasi-steady state eventually disappears with longer periods of
therapy or can be overcome by the use of more potent therapies or
alternative approaches that block the potential spread of virus within
tissues, HIV-1 may never be eradicated," they write.
"...it is sobering to realize," note Dr. Zhang and his colleagues, "that the
so-called highly active antiretroviral therapy is actually not always active
enough. As we strive to eradicate HIV-1 infection or induce a remission, we
must focus on the possibility of further intensifying antiretroviral
treatment, even though current therapies are already toxic, costly and
One bright spot in this picture, says Carl Dieffenbach, Ph.D., associate
director of the Basic Sciences Program in NIAID's Division of AIDS, is that
the technologies developed by these investigators provide "new tools, so
that if we ever have a patient in whom it appears the virus has been
eradicated, we'll be able to verify that." This ability will become
increasingly important, he says, as new and improved drugs shrink the latent
reservoir of HIV even further.
The two studies received additional support from two other components of the
National Institutes of Health (NIH): the National Center for Research
Resources, and the National Heart, Lung and Blood Institute.
NIAID is a component of the 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.
Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
2. M Furtado, et al. Persistence of HIV-1 transcription in peripheral-blood
mononuclear cells in patients receiving potent antiretroviral therapy. The
New England Journal of Medicine 340(21):1614-22 (1999).
3. R Pomerantz. Residual HIV-1 disease in the era of highly active
antiretroviral therapy. The New England Journal of Medicine