"Our findings indicate that an inducible reservoir of HIV exists
in infected patients despite prolonged treatment with highly active
antiretroviral therapy (HAART), and suggest that the time required for
eradication of HIV from the body, if indeed possible, may be
considerably longer than previously predicted," says lead author Tae-
Wook Chun, Ph.D., of NIAID's Laboratory of Immunoregulation (LIR).
Adds senior author Anthony S. Fauci, M.D., NIAID director
and LIR chief, "These results underscore the importance of
developing more potent antiretroviral drugs, as well as treatment
strategies that specifically target latently infected cells that serve
as hiding places for the virus. Although our current armamentarium of
antiretroviral drugs has served many patients well, at least in the
short-term, more progress must be made in the area of HIV
therapeutics if we are to speak of a cure for HIV disease."
Drs. Chun, Fauci and colleagues report their findings in the
Nov. 25 issue of the Proceedings of the National Academy of
Sciences (PNAS). The embargo date for the PNAS paper has been
moved to Nov. 13 at 4:00 p.m. ET to coincide with the publication of
two related reports in the journal Science from the laboratories of
NIAID grantees Robert F. Siliciano, M.D., Ph.D., of Johns Hopkins
University in Baltimore, and Douglas D. Richman, M.D., of the
University of California, San Diego.
In their experiments, Drs. Chun, Fauci and colleagues studied
12 HIV-infected patients who were taking three-drug antiretroviral
regimens consisting of a protease inhibitor (indinavir, ritonavir or
saquinavir) combined with two nucleoside analogues (3TC, d4T, AZT
or ddI). A thirteenth patient received two protease inhibitors and two
nucleoside analogues. These 13 patients had been taking HAART for
an average of 10 months. In addition, four HIV-infected patients
receiving no therapy and one taking 3TC only were included in the
Of the 13 patients receiving HAART, nine had levels of HIV
RNA in their plasma below 500 copies/cubic milliliter (ml), the
detection limit of the branched DNA (bDNA) assay used in the study.
The researchers isolated highly purified, resting CD4+ T cells
from all 18 patients, and used a sensitive laboratory technique called
the polymerase chain reaction to detect HIV DNA in an integrated
form (i.e., inserted into the genes) in cells from each individual.
"Interestingly, levels of integrated HIV DNA were not
significantly higher in untreated patients than in HAART-treated
individuals," notes Dr. Chun. "As others have postulated, this finding
suggests that resting CD4+ T cells with integrated DNA do not decay
rapidly in patients receiving HAART, and therefore may serve as a
stable 'reservoir' of virus."
In addition to integrated HIV DNA, the investigators found
unintegrated DNA in cells from all patients.
"The presence of unintegrated HIV DNA suggests that a low
level of viral replication may continue even in the setting of HAART,"
notes Dr. Fauci. "In HAART-treated patients, we found that levels of
unintegrated HIV DNA were 28 times higher than integrated HIV DNA
levels. This suggests that even when HIV is undetectable in the
plasma, a low degree of viral replication contributes to the
maintenance of a reservoir of HIV-infected CD4+ T cells."
The investigators activated the resting, purified CD4+ T cells
from all study patients and induced replication-competent virus from
each patient's samples, including from the nine with no detectable
virus in their blood. Of note, the virus they induced from the cells of
three of nine HAART-treated patients with undetectable virus was
"syncytium inducing" -- it efficiently killed cells in culture by
causing them to clump together.
"Activation of at least some latently infected resting CD4+ T
cells in patients receiving HAART can result in the production of
cytopathic virus," says Dr. Chun.
Co-authors of Drs. Chun and Fauci include Lieven Stuyver,
Ph.D., of Innogenetics N.V., Ghent, Belgium; Stephanie B. Mizell,
R.N., Linda A. Ehler, R.N., and JoAnn M. Mican, M.D., of the NIAID
Laboratory of Immunoregulation; Michael Baseler, Ph.D., of Science
Applications International Corporation-Frederick, Md.; and Alun L.
Lloyd, Ph.D., and Martin A. Nowak, Ph.D., of the University of Oxford,
NIAID is a component of the National Institutes of Health
(NIH). NIAID conducts and supports research to prevent, diagnose
and treat illnesses such as AIDS and other sexually transmitted
diseases, malaria, tuberculosis, asthma and allergies. NIH is an
agency of the U.S. Department of Health and Human Services.
Chun T-W, et al. Presence of an inducible HIV-1 latent reservoir
during highly active antiretroviral therapy. Proc Natl Acad Sci USA
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