Between a shock and a hard place: challenges and developments in HIV latency reversal

Abstract

Latently infected cells that persist in HIV-infected individuals on antiretroviral therapy (ART) are a major barrier to cure. One strategy to eliminate latency is by activating viral transcription, commonly called latency reversal. Several small non-randomised clinical trials of latency reversing agents (LRAs) in HIV-infected individuals on ART increased viral production, but disappointingly did not reduce the number of latently infected cells or delay time to viral rebound following cessation of ART. More recent approaches aimed at reversing latency include compounds that both activate virus and also modulate immunity to enhance clearance of infected cells. These immunomodulatory LRAs include toll-like receptor agonists, immune checkpoint inhibitors and some cytokines. Here, we provide a brief review of the rationale for transcription-activating and immunomodulatory LRAs, discuss recent clinical trials and some suggestions for combination approaches and research priorities for the future.

Figure 1:. Shock and kill strategy to eliminate latently infected cells.

Following stimulation with a LRA, some latently infected cells will produce only cell-associated HIV RNA (top) while others will go on to become productively infected (bottom). Cells that only produce cell-associated HIV RNA are likely to live, while productively infected cells can either die via cytopathic effects or immune effector mechanisms (common) or survive (uncommon). Env = envelope protein, US = unspliced, SS = singly spliced, MS = multiply spliced.