Editorial Commentary: Reversing Latency in HIV-Infected Patients

Abstract

The inability of combination antiretroviral treatment (cART) to eradicate human immunodeficiency virus (HIV) infection has renewed scientific interest in curative strategies [1]. The primary barrier preventing eradication of HIV by cART is a pool of long-lived latently infected cells of which memory CD4 + T cells appear to be the most important. These latently infected cells harbor integrated proviral DNA capable of resuming HIV expression and fueling viral rebound upon cessation of cART. One strategy to deplete this viral reservoir has been termed “kick and kill,” indicating a 2-step process by which expression of the latent virus is reactivated by a latency-reversing agent followed by elimination of the infected cell by either cell apoptotic/cytolytic mechanism or by immune-mediated clearance. The hunt for pharmacological interventions capable of reactivating HIV from the resting state and hence deliver the first step of this strategy is now on. In the study by Spivak et al in this issue of Clinical Infectious Diseases, the antialcoholism drug disulfiram was tested in 15 virologically suppressed patients with HIV for its ability to reactivate latent HIV. Two questions were asked in this study: First, can disulfiram activate latent HIV as determined by increases in residual viremia? Second, can HIV reactivation with disulfiram lead to a reduction in the size of the latent reservoir? As for the first point, the jury is still out. Overall, during 14 days of disulfiram dosing, there was no significant effect on the level of residual viremia measured by the single-copy assay. Despite this, there are 2 findings supporting the latencyreversing capacity of disulfiram. In 10 patients with measurements 2 hours after the first dose, an increase in residual viremia was observed. Furthermore, during the postdosing phase of the study, an overall increase in viral particle production above baseline was noted. Another class of compounds, the histone deacetylase inhibitors (HDACi), has recently been found to reactivate HIV in CD4 T cells in vivo [2, 3] although these 2 studies investigating the potential of vorinostat to reactive HIV failed to detect any increases in plasma viremia. Unfortunately, the study by