BCL-2 antagonism sensitizes cytotoxic T cell-resistant HIV reservoirs to elimination ex vivo
- 30 April 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (5), 2542-2559
- https://doi.org/10.1172/JCI132374
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-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.Funding Information
- National Institutes of Health (AI31798,AI147845,1UM1AI26617,AI117970)
This publication has 83 references indexed in Scilit:
- Highly Precise Measurement of HIV DNA by Droplet Digital PCRPLOS ONE, 2013
- Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus ReactivationImmunity, 2012
- Studies of HIV-1 latency in an ex vivo model that uses primary central memory T cellsMethods, 2011
- Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiationNature Biotechnology, 2010
- HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferationNature Medicine, 2009
- Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune ControlImmunity, 2008
- The BCL-2 protein family: opposing activities that mediate cell deathNature Reviews Molecular Cell Biology, 2008
- PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infectionThe Journal of Experimental Medicine, 2006
- The Hallmarks of CancerCell, 2000
- Two subsets of memory T lymphocytes with distinct homing potentials and effector functionsNature, 1999