Dataset Information

BCL-2 Inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques

ABSTRACT: The anti-apoptotic molecule BCL-2 favors the maintenance of the CD4+ T-cell reservoir during Human immunodeficiency virus (HIV) infection. We investigated directly in-vivo whether BCL-2 inhibition using venetoclax at the initiation of antiretroviral therapy (ART) would reduce the size of the viral reservoir. Twenty-four SIVmac239-infected rhesus macaques (RMs) were initiated on ART at day 14 post-infection (p.i.), alone or in combination with either 10-day treatment with venetoclax or venetoclax plus CD8α depletion, and followed up to day 294 p.i. A rapid, statistically significant, and sustained reduction in the intact SIV reservoir was observed in venetoclax-treated RMs in blood and lymph nodes (LNs). This reduction was driven by reduced survival and depletion of CD4+ T-cell subsets that critically contribute to the reservoir. CD4+ T-cells that persisted after venetoclax treatment exhibited elevated per-cell levels of BCL-2, reduced expression of pro-apoptotic molecules such as PUMA, increased expression of additional anti-apoptotic molecules, including BCL-xL, and a partial reduction in apoptotic sensitivity in ex vivo assays. These findings provide mechanistic insights for the venetoclax-induced pro-cell death changes in CD4+ T-cells, support the rationale for extended venetoclax dosing, and suggest that combining BCL-2 inhibition with agents targeting additional anti-apoptotic molecules can enhance clearance of the viral reservoir in HIV cure strategies.

ORGANISM(S): Macaca mulatta

PROVIDER: GSE301433 | GEO | 2026/06/28

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:BH3 mimetics were initially designed to induce cancer cell death through targeting key anti-apoptotic members within the BCL-2 family of proteins. Venetoclax, the only FDA-approved BCL-2-specific BH3 mimetic, has demonstrated robust clinical efficacy in killing acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) cells attributed to its direct apoptotic tumor effect. However, little is known regarding the direct effect of venetoclax on tumor infiltrating T cells. Recent studies have reported apoptosis-independent immunomodulatory activities of venetoclax that still are not fully understood. Given the vital role of BCL-2 family proteins in the dynamic processes of T cell activation, differentiation to effector or memory phenotype and contraction, it becomes imperative to dissect the direct effect of BH3 mimetics on T cell functions. We previously demonstrated that murine T cells expanded for 5 days in vitro in the presence of venetoclax acquire adaptive-like reprograming leading to cell death resistance. Further, long-term in vivo treatment with venetoclax results in transcriptional alterations of signaling pathways involved in T cell activation and exhaustion resistance. Herein, we investigate whether this venetoclax-induced T cell reprograming can be employed to improve the efficacy of adoptive T cell therapy. Using murine and human CD19-targeted chimeric antigen receptor (CAR) T cell therapy (CD19CART) as a model, we show that venetoclax treatment during expansion of CD19CARTs prepared from T cells isolated from healthy donors and patients exhibit enhanced antitumor efficacy in vitro and in vivo using pre-clinical xenograft models of lymphoma and leukemia. Mechanistically, bulk and single-cell RNA sequencing analyses reveal that venetoclax treatment during CART manufacturing transcriptionally reprograms CART cells at key T cell signaling (JAK/STAT5, PI3K/AKT, NFKB) and metabolic (PGC1α, OXPHOS, glycolysis) pathways to enhance CAR T cell fitness and durability, mechanisms dependent upon BCL-2 affinity to venetoclax. Our study highlights a possible novel therapeutic approach to induce adaptive anti-apoptotic reprograming to enhance the efficacy of CAR T cell therapy and supports the continued examination of BH3 mimetics as immune modulators.

Dataset Information

BCL-2 Inhibition at antiretroviral therapy initiation reduces the intact SIV reservoir in macaques

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets