HIV-1 Eradication: Early Trials (and Tribulations)

Abstract

Antiretroviral therapy (ART) has rendered HIV-1 infection a manageable illness for those with access to treatment. However, ART does not lead to viral eradication due to the persistence of replication-competent, unexpressed proviruses in long-lived cellular reservoirs. The potential for long-term drug toxicities and the lack of access to ART for most people living with HIV-1 infection have fueled scientific interest in understanding the nature of this latent reservoir. Exploration of HIV-1 persistence at the cellular and molecular level in resting memory CD4+ T cells, the predominant viral reservoir in patients on ART, has uncovered potential strategies to reverse latency. Here, we review recent advances in pharmacologically-based ‘shock and kill’ HIV-1 eradication strategies, including comparative analysis of early clinical trials.

HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal

“…Here, we report optimized methods that enable sensitive and rapid detection of subfemtomolar cell-associated HIV gag p24 protein in HIV-infected CD4 + T cells from ART-suppressed individuals. Quantifying very small amounts of cell-associated viral antigen produced by low numbers of cells from aviremic/low-reservoir HIV + individuals is an important advancement, as viral protein expression is believed to contribute to tissue inflammation and persistent immune activation, and induction is a prerequisite for several investigational immune-mediated "kill" strategies (3)(4)(5)40). The assay can be completed in approximately 1 hour, typically requires 1-2 million peripheral CD4 + T cells from ART-suppressed HIV + individuals, and can be applied to quantify viral protein in cell lysates or culture medium.…”

“…To eliminate the latent reservoir, infected cells must be recognized as harboring virus and then effectively destroyed and cleared. Latency disruption is under intense investigation, and several strategies are being evaluated (3)(4)(5)(6). Recent therapeutic approaches have focused on the use of latency-reversing agents (LRAs) to induce viral transcription, initiate viral translation, and subsequently elicit death through viral cytopathic effects or immune-mediated cell killing ("shock and kill").…”

“…Other agents, such as bromodomain inhibitors and protein kinase C (PKC) agonists, have also been shown to induce viral transcription in vitro and in preclinical models and are under further evaluation as potential clinical HIV "shock" agents (6,(12)(13)(14)(15)(16). Worth noting, the induction of viral protein expression is a prerequisite for several investigational immune-mediated "kill" strategies (3)(4)(5). Broadly neutralizing antibodies are already being used in clinical trials, and other strategies involving the use of other forms of antibodies that target viral protein are currently being developed, highlighting the need for approaches that can demonstrate low-level detection of viral antigens and report on the efficacy of such therapeutic approaches (5,17,18).…”

Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity

“…Agents eliciting global T cell activation were used in the original detection of the reservoir (1, 2) and effectively reverse latency. However, in clinical settings they induce severe adverse reactions by causing systemic release of proinflammatory cytokines (6,7). Although clinical trials using T cell-activating agents such as anti-CD3 and IL-2 have demonstrated transient increases in viremia and changes in HIV-1 intracellular RNA levels (6), this approach has been abandoned in favor of latency-reversing agents (LRAs) that induce HIV-1 transcription without cellular activation.…”

Pharmacologic HIV-1 Nef blockade promotes CD8 T cell–mediated elimination of latently HIV-1–infected cells in vitro

“…Current strategies to eliminate latent reservoirs, such as shock and kill, employ the use of latency reversing agents (LRAs) such as the PKC agonist Bryostatin-1 or histone deacetylase inhibitors (HDACi) romidepsin and panobinostat to induce virus production from latently infected cells in order to facili-tate their elimination by various mechanisms such as viral cytopathic effects or CD8 T cell-mediated clearance (62). However, to our knowledge, no single intervention to date has resulted in a significant reduction of the viral reservoir in vivo while various adverse effects have been observed (62,63).…”