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

AbstractA major barrier towards HIV-1 cure is the presence of a replication-competent latent reservoir that, upon treatment cessation, can spark viral rebound leading to disease progression. Pharmacological reactivation of the latent HIV-1 reservoir with Latency reversing agents (LRAs) is a first step toward triggering reservoir decay. Inhibitors of the BAF-complex, a key repressor of HIV-1 transcription were identified to act as LRAs, and enhanced the effect of other LRAs such as histone deacetylase inhibitors ex-vivo. We repurposed the licensed drug pyrimethamine as a BAF-inhibitor to investigate its in vivo impact on the HIV-1 reservoir of people living with HIV-1 (PLWH). Twenty eight PLWH on suppressive antiviral therapy were randomized in a 1:1:1:1 ratio to receive pyrimethamine; high dose valproic acid; both valproic acid and pyrimethamine; or no intervention for 14 days. The primary endpoint was change in HIV-1 reactivation measured as cell associated (CA)HIV-1 RNA at treatment initiation and at the end of treatment. We observed a rapid, modest and significant increase in CAHIV-1 RNA in CD4+T-cells in response to pyrimethamine exposure, which persisted throughout the 14 day treatment, concomitant with induction of BAF target genes as biomarkers of pyrimethamine activity as well as detected plasma pyrimethamine levels. Valproic acid treatment alone did not lead to increase in CAHIV-1 RNA, nor did valproic acid augment the latency reversal effect of pyrimethamine. Despite demonstrated latency reversal, pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir as determined by a tat/rev limiting dilution assay. Serious adverse events were not observed, although physician-directed treatment adjustments occurred, particularly when combining valproic acid with pyrimethamine. These data underline the need for pharmacovigilance in combinatorial clinical strategies and demonstrate that the BAF inhibitor pyrimethamine reverses HIV-1 latency in vivo in PLWH, substantiating its potential in advancement in clinical studies to target the proviral reservoir. Clinicaltrials.gov:NCT03525730One sentence summaryThis clinical trial shows that the BAF inhibitor pyrimethamine reverses HIV-1 latency in vivo which supports repurposing this drug for cure studies.