Latency-reversing agents: where are we now?

Despite effective antiretroviral therapy (ART), HIV-1 persists in latently infected cells that evade host immunity and can resume viral production upon treatment interruption. To address this challenge, the "shock and kill" strategy aims to use latency-reversing agents (LRAs) to reactivate HIV-1 expression, to allow infected cells to die from viral cytopathic effects or immune-mediated killing.

Several LRAs capable of reactivating HIV-1 ex vivo have been identified over the years, but most induce excessive T-cell activation and are unsuitable for in vivo use. Those advanced to clinical trials safely trigger HIV-1 transcription and modestly reduce reservoir size but have failed to achieve reservoir eradication. This limited in vivo efficacy of LRAs is thought to result from their inability to overcome posttranscriptional blocks, as well as from LRA-induced off-target effects on cellular transcription that can impair immune responses. Recent trials combining LRAs with immune modulators have shown promise in further reducing reservoir size and enhancing immunological control after treatment interruption.

Combining LRAs with immune modulators represents a promising strategy to expose viral reservoirs to immune clearance and advance toward durable, scalable ART-free remission.