期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 5, 页码 2542-2559出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI132374
关键词
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资金
- NIH [AI31798, AI147845]
- Martin Delaney BELIEVE Collaboratory (NIH grant) [1UM1AI26617]
- NIH-funded Center for AIDS Research Grants [P30 AI117970]
- NIH, National Institute of Allergy and Infectious Diseases (NIAID)
- NIH, National Cancer Institute (NCI)
- NIH, National Institute of Child Health and Human Development (NICHD)
- NIH, National Heart, Lung, and Blood Institute (NHLBI)
- NIH, National Institute on Drug Abuse (NIDA)
- NIH, National Institute of Mental Health (NIMH)
- NIH, National Institute on Aging (NIA)
- NIH, Fogarty International Center (FIC)
- NIH, Office of AIDS Research (OAR)
Curing HIV infection will require the elimination of a reservoir of infected CD4(+) T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4(+) T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2(hi) subsets in ex vivo CD4(+) T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.
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