Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice

Arandjelovic, P; Kim, Y; Cooney, JP; Preston, SP; Doerflinger, M; McMahon, JH; Garner, SE; Zerbato, JM; Roche, M; Tumpach, C; Ong, J; Sheerin, D; Smyth, GK; Anderson, JL; Allison, CC; Lewin, SR; Pellegrini, M

Author(s): Arandjelovic, P; Kim, Y; Cooney, JP; Preston, SP; Doerflinger, M; McMahon, JH; Garner, SE; Zerbato, JM; Roche, M; Tumpach, C; Ong, J; Sheerin, D; Smyth, GK; Anderson, JL; Allison, CC; Lewin, SR; Pellegrini, M;
Details: Publication Year 2023-08-23,Volume 4,Issue #9,Page 101178
Journal Title: Cell Reports Medicine
Abstract: HIV-1 persists indefinitely in people living with HIV (PLWH) on antiretroviral therapy (ART). If ART is stopped, the virus rapidly rebounds from long-lived latently infected cells. Using a humanized mouse model of HIV-1 infection and CD4(+) T cells from PLWH on ART, we investigate whether antagonizing host pro-survival proteins can prime latent cells to die and facilitate HIV-1 clearance. Venetoclax, a pro-apoptotic inhibitor of Bcl-2, depletes total and intact HIV-1 DNA in CD4(+) T cells from PLWH ex vivo. This venetoclax-sensitive population is enriched for cells with transcriptionally higher levels of pro-apoptotic BH3-only proteins. Furthermore, venetoclax delays viral rebound in a mouse model of persistent HIV-1 infection, and the combination of venetoclax with the Mcl-1 inhibitor S63845 achieves a longer delay in rebound compared with either intervention alone. Thus, selective inhibition of pro-survival proteins can induce death of HIV-1-infected cells that persist on ART, extending time to viral rebound.
Publisher: Elsevier
Keywords: Humans; Animals; Mice; *hiv-1; *HIV Seropositivity; Bridged Bicyclo Compounds, Heterocyclic/pharmacology/therapeutic use; Disease Models, Animal
Research Division(s): Bioinformatics; Bioinformatics; Cancer Biology And Stem Cells; Infectious Diseases And Immune Defence; Infectious Diseases And Immune Defence; Infectious Diseases and Immune Defence; Bioinformatics
PubMed ID: 37652018
Publisher's Version: https://doi.org/10.1016/j.xcrm.2023.101178
Open Access at Publisher's Site: https://doi.org/10.1016/j.xcrm.2023.101178
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: PIIS2666379123003312.pdf - (3.25MB, application/pdf)

Creation Date: 2023-09-07 09:17:04

Last Modified: 2023-11-20 03:24:03