The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy

Abstract

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.

The efficacy and tolerability of latency-reversing agents in reactivating the HIV-1 reservoir in clinical studies: a systematic review

“…LRAs were combined with other therapies in six studies (vorinostat with maraviroc, vorinostat with tamoxifen, pyrimethamine with valproic acid, vorinostat with disulfiram, IL-7 with maraviroc, and nivolumab with ipilimumab). 27 , 39 , 42 , 52 , 55 , 56 Increase in CA US HIV-1 RNA was observed in all combinations except IL-7 with maraviroc, but none exhibited synergy between LRAs.…”

“…Significant increases from baseline CA US HIV-1 RNA were found in all HDACis except for valproic acid monotherapy. 39 Of the eleven studies with transcription activators, CA US HIV-1 RNA increases were found in five studies, 34 , 41 , 44 , 48 , 49 with maraviroc 48 and disulfiram 41 having the best evidence for their effect. Furthermore, all four immune checkpoint inhibitors 54 , 55 , 56 , 57 and two vaccine studies 59 , 60 demonstrated CA US HIV-1 RNA increases.…”

“… 25 , 37 , 46 , 50 Seven studies (panobinostat, 30 romidepsin 33 , pyrimethamine, 39 valproic acid, 39 vorinostat, 42 pembrolizumab, 57 nivolumab and ipilimumab 55 , 56 ) quantified the increase within 24 h after the first dose and reported this result separately, instead of as a pooled analysis together with changes observed after later administrations following the first dose. A significant, over 2-fold change from baseline, within this 24 h window after the first dose, was reported for pyrimethamine 39 (2.1 after 6 h), romidepsin 33 (>2.5 after 4 h) and panobinostat (2.4 after 2 h). 30 A significant effect below a 2-fold change was observed in nivolumab and ipilimumab.…”

PCID2 dysregulates transcription and viral RNA processing to promote HIV-1 latency

“…48 hours after transfection, cells were collected and lysed in TRI reagent (Sigma) and total RNA was isolated as described before. 58 We then DNAse treated the RNA and synthetized cDNA using, respectively, DNAse I amplification grade kit (Invitrogen) and SuperScript II reverse transcriptase (Invitrogen) following the provided protocols.…”

“…To analyse the change in US and CS vRNA we performed a nested qPCR assay targeting Gag (US vRNA) and Tat-Rev (CS vRNA) as described before 58 , 59 with minor modifications. Briefly, for pre-amplification of US and CS vRNA 10 μL of diluted cDNA were used in a final volume of 25 μL using Platinum™ Taq DNA polymerase kit (Invitrogen) and nested US forward and reverse 1 primers for US vRNA detection or nested CS forward and reverse primers for CS vRNA detection ( Table 2 ).…”