Quantifying Residual HIV-1 Replication and Decay of the Latent Reservoir in Patients on Seemingly Effective Combination Antiretroviral Therapy
authors include: L Zhang and others from Aaron Diamond AIDS Research Center; K & P Tenner-Racz from Hamburg, Germany; A Perelson from Los Alamos Labs, New Mexico.

Report prepared by Jules Levin

L Zhang reported at the Retrovirus Conference on a small study group of 8 individuals treated during acute infection (within 90 days of primary HIV infection) with HAART (2 NRTIs+ 1 or 2 protease inhibitors). All 8 individuals were suppressed below 50 copies/ml for 2-3 years without any interruption. That is, there was no blip of viral load above 50 copies/ml during the entire treatment period. Proviral DNA sequences from patient's PBMC were analyzed and the sequence evolution was used as evidence for residual HIV replication. He found no evidence of virus replication in 6/8 individuals. However, in the remaining 2 patients he found evidence of envelope evolution indicative of ongoing viral replication, in the absence of drug-resistant genotypes. Extensive in situ hybridization studies involving 175 samples from GALT (gut associated lymph tissue) tonsils and lymph node biopsies on one of the 2 cases demonstrated 13 positive samples (2 GALT, 5 tonsil, 6 lymph node) while 162 samples were negative for HIV. This provides additional evidence for persistent viral replication, and also showed where the productively infected cells were: lymph node, tonsil, colon. The authors said that these findings suggest that in some cases, treatment intensification may be necessary to achieve complete suppression of HIV replication. My question is--can these encouraging results be expected from chronically infected individuals? I don't think we know the answer to this question, but it may be possible.

Zhang reported on a second line of investigation in this study. Two independent approaches were taken to estimate the decay rate of replication-competent HIV harbored latently in resting CD4 memory cells. One was based on the decay in parental proviral sequences identified at the primary infection, and the other was a direct measurement of the size of the latent reservoir using a limited-dilution boosted culture technique. The decline or decay slope was quite comparable as measured by both techniques. Both approaches yielded a decay half life of about 6 months (7-10) for the replication competent virus in the resting memory CD4s. It is estimated that it would take about 5-7 years for this reservoir to decay.

Robert Siliciano, from Johns Hopkins University, discovered and was the first to report the finding of this latent reservoir. He studied chronically infected individuals and did not detect decay in the latent resrvoir in resting CD4 memory cells. The discrepancy between Aaron Diamond and Siliciano is that Zhang found decay in individuals with acute infection and Siliciano found no decay in individuals with chronic infection. But, at the World AIDS Conference in Geneva, Siliciano said eradication of this reservoir is possible. I think he may have been referring to a situation similar to the one described by Zhang.

Even if eradication of this reservoir is possible which remains questionable, researchers report virus reservoirs in genital secretions, the brain, HIV-RNA in PBMCs, and CSF. In an effort to meet this challenge ongoing research is focusing on the capacity of immune based therapies to boost the immune system enough to control HIV despite the existence of reservoirs. Remune and other vaccines and cytokines are being researched in this effort. At the Retrovirus Conference, Briggette Autran discussed how IL-12 may be useful in this effort. Anthony Fauci's lab at the NIH reported at Retrovirus that IL-2 may be helpful in driving HIV out of the reservoir of CD4 memory cells described above.