The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo

Abstract

Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 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-1 RNA 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 quantifiable 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, romidepsin safely 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 Registrationclinicaltrials.gov NTC02092116

Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

“…Although all investigated LRAs showed increased virus transcription, no changes in the latent-reservoir size were detected after the use of LRA in vivo (14,(18)(19)(20) or in vitro (24). One reason could be the short time during which LRAs were given to ART patients (ranging from 8 weeks for panobinostat to 3 weeks for romidepsin and 3 days for disulfiram), making the detection of reservoir decay problematic.…”

“…An increase in plasma HIV RNA was seen with panobinostat (19), romidepsin (20), and disulfiram (14), although in the panobinostat trial (19) this was demonstrated by a nonquantitative assay. Changes in HIV transcription have been demonstrated in all trials by showing an increase in the level of cell-associated HIV RNA (CA RNA) in total and resting CD4 ϩ T cells (21).…”

“…Various latencyreversing agents (LRAs) have been investigated, including drugs that trigger the NF-B activation pathway, such as prostratin (10) and bryostatin (11) analogues; BET inhibitors enhancing the binding of the viral Tat protein to the HIV TAR element (12); disulfiram (13,14); and histone deacetylase inhibitors (HDACi), like valproic acid (15,16), vorinostat (17,18), panobinostat (19), and romidepsin (20), that act as epigenetic modifiers. The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy.…”

“…The HDACi were the first compounds to enter clinical trials, given the extensive data on their toxicity from studies in individuals with malignancy. However, all clinical trials of HDACi have demonstrated no decline in the frequency of latently infected cells (15,(18)(19)(20).…”

“…We use the results of the panobinostat (19) and romidepsin (20) trials to illustrate the effect of the interplay of the HIV reactivation rate and death on the US HIV RNA level. For example, although the CA RNA tripled in the presence of panobinostat, our model suggests that the frequency of transcription activation in time increased by less than 10%, while the much larger increase in the number of cells with reactivated HIV was caused by their long life span.…”