INTRODUCTION
infection
INFECTION, VALPROIC ACID, DECAY
These authors contributed equally to this work.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 antiprotozoal pyrimethamine reactivates latent HIV in vivo and can be used in the search for an HIV cure.Despite markedly improved treatment prospects brought about by combination antiretroviral therapy (cART), an infection with HIV-1 remains a chronic condition that, with few exceptions, necessitates lifelong cART. A pool of long-lived CD4One of the key approaches currently proposed to eradicate the latent HIV-1 reservoir in PLWH is to pharmacologically reverse latency via latency reversing agents (LRAs). Elimination of the reactivated reservoir cells could then be triggered by intrinsic proapoptotic pathways or via extracellular immune cell–mediated mechanisms (The multitude of LRAs that have been identified through mechanism-based approaches or large-scale screening of compound libraries can be categorized based on distinct molecular and pharmacological targets (Our preclinical studies identified BRG–Brahma associated factor (BAF) complex inhibitors (BAFi) as a novel LRA class, which we demonstrated enhanced the activity of other LRA classes (To study the efficacy of BAF complex inhibition by pyrimethamine to reactivate the HIV-1 reservoirs in PLWH, we conducted a proof-of-concept, randomized controlled clinical trial [LRAs United as a Novel Anti-HIV strategy (LUNA), 