Peer-reviewedCC BY-NC-ND 4.0Nature Microbiology
BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques
11 affiliations
- 1Division of Microbiology and Immunology, Emory National Biomedical Research Center, Emory University, Atlanta, GA USA
- 2AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD USA
- 3Division of Animal Resources, Emory National Biomedical Research Center, Emory University, Atlanta, GA USA
- 4Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA USA
- 5Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA USA
- 6Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina UNC Eshelman School of Pharmacy, Chapel Hill, NC USA
- 7Accelevir Diagnostics, Baltimore, MD USA
- 8Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY USA
- 9Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY USA
- 10Division of Infectious Diseases, Mayo Clinic, Rochester, MN USA
- 11Department of Molecular Medicine, Mayo Clinic, Rochester, MN USA
Abstract
The anti-apoptotic molecule BCL-2 favours the maintenance of the CD4+ T-cell reservoir during HIV infection. Whether inhibition of BCL-2 can lead to long-term reduction of the HIV reservoir is unclear. Here we initiated antiretroviral therapy (ART) in 24 simian immunodeficiency virus (SIV)-infected rhesus macaques at 14 days post infection (p.i.), alone or combined with a 10-day treatment of venetoclax or venetoclax and CD8α depletion, with a follow-up to day 294 p.i. We report a rapid and sustained reduction of the intact SIV reservoir in venetoclax-treated rhesus macaques in blood and lymph nodes. CD4+ T cells that persisted after venetoclax treatment showed partial reduction in apoptotic sensitivity in ex vivo assays. These exhibited elevated expression of anti-apoptotic BCL-2 and BCL-xL, and showed reduced expression of pro-apoptotic molecules such as PUMA. These findings support the rationale for extended venetoclax dosing and suggest that combining BCL-2 inhibition with agents targeting additional anti-apoptotic molecules could enhance clearance of the viral reservoir in HIV cure strategies.
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BibTeX
@article{salinas2026bcl2,
title = {{BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques}},
author = {Tomas Raul Wiche Salinas and Justin Harper and Claire Deleage and Kevin Nguyen and James Auger and Hannah R. Flores and Sandeep R. Kaushik and Amelia C. Wilkes and Rachelle L. Stammen and Jennifer S. Wood and Kirk A. Easley and Sydney Nelson and Gregory K. Tharp and Steven E. Bosinger and Mackenzie L. Cottrell and Emek Kose and Taina T. Immonen and Jeffrey D. Lifson and Gregory M. Laird and Brandon F. Keele and R. Brad Jones and Andrew D. Badley and Guido Silvestri and Deanna A. Kulpa and Mirko Paiardini},
journal = {Nature Microbiology},
year = {2026},
month = sep,
doi = {10.1038/s41564-026-02464-7},
url = {https://doi.org/10.1038/s41564-026-02464-7},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - BCL-2 inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques
AU - Tomas Raul Wiche Salinas
AU - Justin Harper
AU - Claire Deleage
AU - Kevin Nguyen
AU - James Auger
AU - Hannah R. Flores
AU - Sandeep R. Kaushik
AU - Amelia C. Wilkes
AU - Rachelle L. Stammen
AU - Jennifer S. Wood
AU - Kirk A. Easley
AU - Sydney Nelson
AU - Gregory K. Tharp
AU - Steven E. Bosinger
AU - Mackenzie L. Cottrell
AU - Emek Kose
AU - Taina T. Immonen
AU - Jeffrey D. Lifson
AU - Gregory M. Laird
AU - Brandon F. Keele
AU - R. Brad Jones
AU - Andrew D. Badley
AU - Guido Silvestri
AU - Deanna A. Kulpa
AU - Mirko Paiardini
PY - 2026
DA - 2026/09/03
JO - Nature Microbiology
DO - 10.1038/s41564-026-02464-7
UR - https://doi.org/10.1038/s41564-026-02464-7
AB - The anti-apoptotic molecule BCL-2 favours the maintenance of the CD4+ T-cell reservoir during HIV infection. Whether inhibition of BCL-2 can lead to long-term reduction of the HIV reservoir is unclear. Here we initiated antiretroviral therapy (ART) in 24 simian immunodeficiency virus (SIV)-infected rhesus macaques at 14 days post infection (p.i.), alone or combined with a 10-day treatment of venetoclax or venetoclax and CD8α depletion, with a follow-up to day 294 p.i. We report a rapid and sustained reduction of the intact SIV reservoir in venetoclax-treated rhesus macaques in blood and lymph nodes. CD4+ T cells that persisted after venetoclax treatment showed partial reduction in apoptotic sensitivity in ex vivo assays. These exhibited elevated expression of anti-apoptotic BCL-2 and BCL-xL, and showed reduced expression of pro-apoptotic molecules such as PUMA. These findings support the rationale for extended venetoclax dosing and suggest that combining BCL-2 inhibition with agents targeting additional anti-apoptotic molecules could enhance clearance of the viral reservoir in HIV cure strategies.
SN - 2058-5276
ER -