The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

TLDR

Pharmacologic activation of latent HIV‑1 proviruses in the presence of ART has been proposed as a step toward cure, but human approaches have yielded mixed results. The study aimed to determine whether intravenous romidepsin could reverse HIV‑1 latency in aviremic adults on ART. Six participants received 5 mg/m² romidepsin weekly for three weeks in a phase Ib/IIa trial. Romidepsin rapidly increased histone acetylation and HIV‑1 transcription, producing detectable plasma viremia in five of six patients without diminishing HIV‑specific T cells or cytokine production, and was well tolerated with only grade 1–2 adverse events, demonstrating safe reversal of HIV‑1 latency in vivo. Trial registration: clinicaltrials.gov NTC02092116.

Abstract

Pharmacologically-induced activation of replication competent proviruses from latency inthe presence of antiretroviral treatment (ART) has been proposed as a step towards curingHIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans haveyielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremicHIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7–7.7 relative to baseline) within the first hours following each romidepsin administration.Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1RNA increased significantly from baseline during treatment (range of fold-increase: 2.4–5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifi-able levels at multiple post-infusion time-points in 5 of 6 patients (range 46–103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1–2) were consistent with the known side effects of romidepsin. In conclusion, romidepsinsafely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. TRIAL REGISTRATION: clinicaltrials.gov NTC02092116