HIV Persists and Can Replicate Despite Prolonged Combination Therapy
HIV persists and can replicate in patients who have no detectable virus in their blood as a result of combination antiretroviral therapy, according to a new report from researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues.
"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 study population.
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, England.
Reference: Chun T-W, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997;94:13193-7.
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