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HIV Latency: still trying to figure it out; is HIV curable?
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Report by David Margolis, MD, University of Texas, Southwestern Medical Center
Resting CD4+ T cells comprise the best defined reservoir of HIV-1 latent infection. O'Doherty contributed to the ongoing debate on how these reservoirs are formed. A leading hypothesis is that latent reservoirs form when activated T cells are infected as they return to a resting state. Another hypothesis is that infection proceeds in resting CD4+ T cells but to a point prior to integration of the virus in the genome. A transient stimulus (eg. cytokines) may then allow integration to occur without full cell activation and viral production. A third hypothesis is that integration and latent infection can occur in resting CD4+ T cells without any stimuli. O'Doherty (Abstr. 123LB, 427) put forward evidence supporting the "third way." In her experiments large numbers of virions are deposited onto the cell surface with centrifugal force. Unintegrated reverse transcripts of HIV genomic DNA and integrated HIV DNA are detected by sensitive PCR techniques. 3 of 10 cells treated this way contain HIV genomes, and in 1 of 10 that genome has integrated into the host DNA. As in this system at least 1% of the CD4+ T cells are capable of productive infection, it appears that not all the integrants can produce virus, a feature also consistent with the prior findings of other groups. While latency may be established through one or all three of these mechanisms, one thing that all can agree on is that getting rid of latently infected CD4 cells could be a good thing. As had been suggested initially by the Zack lab in studies using a murine model, the Pomerantz lab reported that phorbol esters or IL7 treatment allowed the recovery of HIV from patients on HAART (Abstract. 423, 424). IL7 induced viral outgrowth in O’Doherty’s model as well. Margolis and colleagues showed that treating the resting CD4 cells of HAART-suppressed patients with the widely used drug valproate allowed recovery of latent HIV (Abstract 427c). Vitetta and colleagues reported an alternate approach in cultured patient cells, using an antibody to eliminate all resting cells, and thereby latent HIV infection (Abstract 427b). Intensification of standard HAART with abacavir (Abstract 52), however, did not reduce the latent resting cell reservoir.
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