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

Henrieke A.B. Prins; Raquel Crespo; Cynthia Lungu; Shringar Rao; Letao Li; Ronald J. Overmars; Grigorius Papageorgiou; Yvonne M. Mueller; Mateusz Stoszko; Tanvir Hossain; Tsung Wai Kan; Bart J.A. Rijnders; Hannelore I. Bax; Eric C.M. van Gorp; Jan L. Nouwen; Theodora E.M.S. de Vries-Sluijs; Carolina A.M. Schurink; Mariana de Mendonça Melo; Els van Nood; Angela Colbers; David Burger; Robert Jan Palstra; Jeroen J.A. van Kampen; David A.M.C. van de Vijver; Thibault Mesplède; Peter D. Katsikis; Rob A. Gruters; Birgit C.P. Koch; Annelies Verbon; Tokameh Mahmoudi; Casper Rokx

doi:10.1126/sciadv.ade6675

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

Henrieke A.B. Prins, Raquel Crespo, Cynthia Lungu, Shringar Rao, Letao Li, Ronald J. Overmars, Grigorius Papageorgiou, Yvonne M. Mueller, Mateusz Stoszko, Tanvir Hossain, Tsung Wai Kan, Bart J.A. Rijnders, Hannelore I. Bax, Eric C.M. van Gorp, Jan L. Nouwen, Theodora E.M.S. de Vries-Sluijs, Carolina A.M. Schurink, Mariana de Mendonça Melo, Els van Nood, Angela ColbersDavid Burger, Robert Jan Palstra, Jeroen J.A. van Kampen, David A.M.C. van de Vijver, Thibault Mesplède, Peter D. Katsikis, Rob A. Gruters, Birgit C.P. Koch, Annelies Verbon, Tokameh Mahmoudi^*, Casper Rokx^*

^*Corresponding author for this work

Divison of Internal Medicine and Dermatology

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	eade6675
Journal	Science advances
Volume	9
Issue number	11
DOIs	https://doi.org/10.1126/sciadv.ade6675
Publication status	Published - Mar 2023

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Prins, H. A. B., Crespo, R., Lungu, C., Rao, S., Li, L., Overmars, R. J., Papageorgiou, G., Mueller, Y. M., Stoszko, M., Hossain, T., Kan, T. W., Rijnders, B. J. A., Bax, H. I., van Gorp, E. C. M., Nouwen, J. L., de Vries-Sluijs, T. E. M. S., Schurink, C. A. M., de Mendonça Melo, M., van Nood, E., ... Rokx, C. (2023). The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy. Science advances, 9(11), Article eade6675. https://doi.org/10.1126/sciadv.ade6675

@article{c01b52310aa54e6bab6e54e6eda4b4a0,

title = "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.",

author = "Prins, {Henrieke A.B.} and Raquel Crespo and Cynthia Lungu and Shringar Rao and Letao Li and Overmars, {Ronald J.} and Grigorius Papageorgiou and Mueller, {Yvonne M.} and Mateusz Stoszko and Tanvir Hossain and Kan, {Tsung Wai} and Rijnders, {Bart J.A.} and Bax, {Hannelore I.} and {van Gorp}, {Eric C.M.} and Nouwen, {Jan L.} and {de Vries-Sluijs}, {Theodora E.M.S.} and Schurink, {Carolina A.M.} and {de Mendon{\c c}a Melo}, Mariana and {van Nood}, Els and Angela Colbers and David Burger and Palstra, {Robert Jan} and {van Kampen}, {Jeroen J.A.} and {van de Vijver}, {David A.M.C.} and Thibault Mespl{\`e}de and Katsikis, {Peter D.} and Gruters, {Rob A.} and Koch, {Birgit C.P.} and Annelies Verbon and Tokameh Mahmoudi and Casper Rokx",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.",

year = "2023",

month = mar,

doi = "10.1126/sciadv.ade6675",

language = "English",

volume = "9",

number = "11",

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Prins, HAB, Crespo, R, Lungu, C, Rao, S, Li, L, Overmars, RJ, Papageorgiou, G, Mueller, YM, Stoszko, M, Hossain, T, Kan, TW, Rijnders, BJA, Bax, HI, van Gorp, ECM, Nouwen, JL, de Vries-Sluijs, TEMS, Schurink, CAM, de Mendonça Melo, M, van Nood, E, Colbers, A, Burger, D, Palstra, RJ, van Kampen, JJA, van de Vijver, DAMC, Mesplède, T, Katsikis, PD, Gruters, RA, Koch, BCP, Verbon, A, Mahmoudi, T & Rokx, C 2023, 'The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy', Science advances, vol. 9, no. 11, eade6675. https://doi.org/10.1126/sciadv.ade6675

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

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 - http://www.scopus.com/inward/record.url?scp=85150313284&partnerID=8YFLogxK

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 -

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

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