TY - JOUR
T1 - The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy
AU - Prins, Henrieke A.B.
AU - Crespo, Raquel
AU - Lungu, Cynthia
AU - Rao, Shringar
AU - Li, Letao
AU - Overmars, Ronald J.
AU - Papageorgiou, Grigorius
AU - Mueller, Yvonne M.
AU - Stoszko, Mateusz
AU - Hossain, Tanvir
AU - Kan, Tsung Wai
AU - Rijnders, Bart J.A.
AU - Bax, Hannelore I.
AU - van Gorp, Eric C.M.
AU - Nouwen, Jan L.
AU - de Vries-Sluijs, Theodora E.M.S.
AU - Schurink, Carolina A.M.
AU - de Mendonça Melo, Mariana
AU - van Nood, Els
AU - Colbers, Angela
AU - Burger, David
AU - Palstra, Robert Jan
AU - van Kampen, Jeroen J.A.
AU - van de Vijver, David A.M.C.
AU - Mesplède, Thibault
AU - Katsikis, Peter D.
AU - Gruters, Rob A.
AU - Koch, Birgit C.P.
AU - Verbon, Annelies
AU - Mahmoudi, Tokameh
AU - Rokx, Casper
N1 - Publisher Copyright:
Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85150313284
U2 - 10.1126/sciadv.ade6675
DO - 10.1126/sciadv.ade6675
M3 - Article
C2 - 36921041
AN - SCOPUS:85150313284
VL - 9
JO - Science advances
JF - Science advances
IS - 11
M1 - eade6675
ER -