Objectives:

A small pool of long-lived memory CD4+ T cells harboring the retroviral genome is one main obstacle to HIV eradication. We tested the impact of the gold compound, auranofin, on phenotype and viability of CD4+ T cells in vitro, and on persistence of lentiviral reservoir cells in vivo.

Design:

In-vitro and in-vivo study. The pro-differentiating effect of auranofin was investigated in human primary CD4+ T cells, and its capacity to deplete the viral DNA (vDNA) reservoir was tested in a pilot study involving six SIVmac251-infected macaques with viral loads stably suppressed by antiretroviral therapy (ART)(tenofovir/emtricitabine/raltegravir). The study was then amplified by intensifying ART using darunavir/r and including controls under intensified ART alone. All therapies were eventually suspended and viro-immunological parameters were monitored over time.

Methods:

Cell subpopulations were quantitated by flow cytometry following proper hematological analyses. Viral load and cell-associated vDNA were quantitated by Taqman real-time PCR.

Results:

In naïve, central memory and transitional memory CD4+ T cells, auranofin induced both phenotype changes and cell death which were more pronounced in the memory compartment. In the pilot study in vivo, auranofin transiently decreased the cell-associated vDNA reservoir in peripheral blood. When ART was intensified, a sustained decrease in vDNA was observed only in auranofin-treated monkeys but not in controls treated with intensified ART alone. After therapy suspension, only monkeys that had received auranofin showed a deferred and subsequently blunted viral load rebound.

Conclusion:

These findings represent a first step towards a remission of primate lentiviral infections.

Introduction

Despite the potency of antiretroviral drugs to inhibit viral replication, current antiretroviral treatments do not eradicate HIV from the body [1, 2]. Memory CD4+ T cells harboring a transcriptionally silent but replication-competent provirus play a major role in HIV persistence [3–5]. HIV primarily persists in long-lived central memory (T CM) and transitional memory (T TM) CD4+ T cells through T-cell survival and continuous low-level proliferation [6]. As opposed to short-lived effector CD4+ T cells (T EM), T CM and T TM cells express CD27 along with CD28 [7–9]. Both receptors share the capacity to promote survival of the dividing cells [10]. CD27 is particularly important for maintenance of T-cell memory [10–12] and differentiation into a Th1 (IFN-γ+) phenotype [13], although it does not seem to play a major role in maintenance of naive T cells (T N) and T-cell generation from thymic precursors [11].