BCL-2 antagonism sensitizes cytotoxic T cell-resistant HIV reservoirs to elimination ex vivo.

Abstract

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-2hi 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.

• Authors: Yanqin Ren, Szu Han Huang, Shabnum Patel, Winiffer D Conce Alberto, Dean Magat, Dughan Ahimovic, Amanda B Macedo, Ryan Durga, Dora Chan, Elizabeth Zale, Talia M Mota, Ronald Truong, Thomas Rohwetter, Chase D McCann, Colin M Kovacs, Erika Benko, Avery Wimpelberg, Christopher Cannon, W David Hardy, Alberto Bosque, Catherine M Bollard, R Brad Jones
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 130 Issue 5 Pg. 2542-2559 (05 01 2020) ISSN: 1558-8238 [Electronic] United States
• PMID: 32027622 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• venetoclax

Topics

• Adult
• Antiretroviral Therapy, Highly Active
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• CD4-Positive T-Lymphocytes (classification, immunology, virology)
• Coculture Techniques
• Combined Modality Therapy
• Cytotoxicity, Immunologic (genetics)
• Disease Reservoirs (virology)
• Female
• Gene Expression Profiling
• HIV (immunology, pathogenicity, physiology)
• HIV Infections (immunology, therapy, virology)
• Humans
• In Vitro Techniques
• Male
• Middle Aged
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, immunology)
• Sulfonamides (pharmacology)
• T-Lymphocytes, Cytotoxic (immunology, virology)
• Virus Latency (drug effects)