TY - JOUR
T1 - Venetoclax, alone and in combination with the BH3 mimetic S63845, depletes HIV-1 latently infected cells and delays rebound in humanized mice
AU - Arandjelovic, Philip
AU - Kim, Youry
AU - Cooney, James P.
AU - Preston, Simon P.
AU - Doerflinger, Marcel
AU - McMahon, James H.
AU - Garner, Sarah E.
AU - Zerbato, Jennifer M.
AU - Roche, Michael
AU - Tumpach, Carolin
AU - Ong, Jesslyn
AU - Sheerin, Dylan
AU - Smyth, Gordon K.
AU - Anderson, Jenny L.
AU - Allison, Cody C.
AU - Lewin, Sharon R.
AU - Pellegrini, Marc
N1 - Funding Information:
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. P.A. C.C.A. and M.P. designed research in the mouse model. Y.K. J.L.A. and S.R.L. designed research using primary human peripheral blood mononuclear cells (PBMCs). J.H.M. provided samples from PLWH on ART. P.A. C.C.A. S.P.P. Y.K. J.L.A. S.E.G. J.M.Z. C.T. J.O. and J.P.C. performed experiments. P.A. C.C.A. Y.K. M.R. D.S. J.L.A. G.K.S. S.R.L. and M.P. analyzed and interpreted the data. P.A. and M.P. wrote the paper. All authors reviewed and contributed to the manuscript. The Walter and Eliza Hall Institute receives milestone and royalty payments related to venetoclax and has a commercial collaboration with Servier with respect to Mcl-1 inhibitors under which it may receive future payments. M.P. is eligible for financial benefits related to these payments. S.R.L. has received investigator-initiated, industry-funded research support from Merck Sciences, Gilead Sciences, and ViiV and provision of reagents from Infinity Pharmaceuticals, Merck Sciences, and BMS for investigator-initiated research. S.R.L. and J.L.A. have research collaborations with Merck Sciences unrelated to this work. We support inclusive, diverse, and equitable conduct of research.
Funding Information:
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 .
Publisher Copyright:
© 2023 The Authors
PY - 2023/9/19
Y1 - 2023/9/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85171195801&partnerID=8YFLogxK
U2 - 10.1016/j.xcrm.2023.101178
DO - 10.1016/j.xcrm.2023.101178
M3 - Article
C2 - 37652018
AN - SCOPUS:85171195801
SN - 2666-3791
VL - 4
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 9
M1 - 101178
ER -
