Abstract
BackgroundHIV infection persists despite antiretroviral treatment (ART) and is reignited as soon as therapies are suspended. This vicious cycle is fueled by the persistence of viral reservoirs that are invulnerable to standard ART protocols, and thus therapeutic agents able to target these reservoirs are needed. One such agent, auranofin, has recently been shown to decrease the memory T-cell reservoir in chronically SIVmac251-infected macaques. Moreover, auranofin could synergize with a fully suppressive ART protocol and induce a drug-free post-therapy containment of viremia.ResultsWe administered buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis currently in clinical trials for cancer, in combination with auranofin to chronically SIVmac251-infected macaques under highly-intensified ART (H-iART). The ART/auranofin/BSO therapeutic protocol was followed, after therapy suspension, by a significant decrease of viral RNA and DNA in peripheral blood as compared to pre-therapy levels. Drug-free post-therapy control of the infection was achieved in animals with pre-therapy viral loads ranging from values comparable to average human set points to levels largely higher. This control was dependent on the presence CD8+ cells and associated with enhanced levels of cell-mediated immune responses.ConclusionsThe level of post-therapy viral set point reduction achieved in this study is the largest reported so far in chronically SIVmac251-infected macaques and may represent a promising strategy to improve over the current “ART for life” plight.
Highlights
Human immunodeficiency virus (HIV) infection persists despite antiretroviral treatment (ART) and is reignited as soon as therapies are suspended
Combined auranofin/highlyintensified ART (H-iART) treatment induces a profound rearrangement in the CD4+ T-cell subpopulations We first analyzed the combined effects of auranofin and a five-antiretroviral drug regimen, i.e. H-iART, on the Tlymphocyte subpopulation dynamics and on the immunological post-therapy control of viremia
The combined auranofin/H-iART therapy induced a significant reduction in the percentages of naïve cells (TN; Figure 1A) and a parallel reduction in the T naïve (TN) absolute numbers, the latter did not reach statistical significance (Figure 1B)
Summary
HIV infection persists despite antiretroviral treatment (ART) and is reignited as soon as therapies are suspended. This vicious cycle is fueled by the persistence of viral reservoirs that are invulnerable to standard ART protocols, and therapeutic agents able to target these reservoirs are needed. One such agent, auranofin, has recently been shown to decrease the memory T-cell reservoir in chronically SIVmac251-infected macaques. The sites for the persistence of latent HIV-1 during ART lie in the presence of long-lived viral reservoirs (mainly the memory CD4+ T-cell subpopulations), which harbor silent copies of proviral DNA that cannot be targeted by drugs or the immune system. Candidate anti-reservoir strategies, targeting one or many of these viral reservoirs, may exert a profound impact on the viral set point once ART is suspended [11]
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