Curing HIV infection will require the elimination of a reservoir of infected CD4+ T-cells that persists despite HIV-specific CTL responses. While 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. We explored the hypothesis that this resistance is mediated by BCL-2 family proteins, which can antagonize CTL-induced apoptosis. We show that the reactivatable HIV reservoir is disproportionately present in BCL-2hi CD4+ T-cells, which are relatively resistant to CTL. BCL-2/BCL-XL antagonists were sufficient for inducing the elimination of HIV-infected cells from a primary-cell model of latency, but did not drive reductions in ex vivo viral reservoirs when tested either alone or with a latency reversing agent (LRA). The triple combination of LRAs, HIV-specific T-cells, and a BCL-2 antagonist uniquely enabled depletions in ex vivo viral reservoirs, providing rationale for novel therapeutic approaches targeting HIV cure.
Keywords: HIV reservoir, HIV eradication, BCL-2, BCL-2 antagonist, BCL-XL antagonist, HIV-Specific T cells, resistance to CTL killing
Ren, Yanqin and Huang, Szu Han and Patel, Shabnum and Magat, Dean and Macedo, Amanda B. and Durga, Ryan and Zale, Elizabeth and Mota, Talia and Truong, Ronald and Rohwetter, Thomas and McCann, Chase D. and Kovacs, Colin C. and Benko, Erika and Wimpelberg, Avery and Cannon, Christopher and Hardy, W. David and Bosque, Alberto and Bollard, Catherine M. and Jones, R. Brad, BCL-2 Antagonism Sensitizes CTL-Resistant HIV Reservoirs to Elimination
Ex Vivo (May 9, 2019). Available at SSRN: https://ssrn.com/abstract=3385137 or http://dx.doi.org/10.2139/ssrn.3385137
This version of the paper has not been formally peer reviewed.
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