Journal article
Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice
P Arandjelovic, Y Kim, JP Cooney, SP Preston, M Doerflinger, JH McMahon, SE Garner, JM Zerbato, M Roche, C Tumpach, J Ong, D Sheerin, GK Smyth, JL Anderson, CC Allison, SR Lewin, M Pellegrini
Cell Reports Medicine | Published : 2023
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 mod..
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Grants
Awarded by Bristol-Myers Squibb
Funding Acknowledgements
We thank Merle Dayton for assistance with facial vein injections, the Australian Red Cross Blood Service for supplying buffy coats, and Melissa Hobbs for technical support. We also thank PLWH for generously providing blood samples for this study. We are grateful to Ajantha Solomon, Ashanti Dantanarayana, Surekha Tennakoon, Socheata Chea, Judy Chang, Thomas Rasmussen, Barbara Scher, and Jared Stern at The University of Melbourne for providing clinical information, samples from PLWH, and technical support, plus Tina Luke from the Doherty Institute Flow Cytometry Facility for support. This work was supported by the National Health and Medical Research Council Australia (grants 1006592, 1045549, and 1065626 to M.P.; 1052979 and 118864 to S.R.L.; and 1154970 to G.K.S.); the Sylvia & Charles Viertel Senior Medical Research Fellowship (M.P.); an Australian Centre for HIV and Hepatitis Virology Research 2018 grant (J.L.A. and S.R.L.); the Victorian State Government Operational Infrastructure Support; and the Independent Research Institutes Infrastructure Support Scheme of the Australian Government National Health and Medical Research Council.