Prime, Kick, and Kill: Establishing a Proof of Concept for a Novel Approach to Purging Latent Reservoirs of Human Immunodeficiency Virus-1
Open AccessLatent reservoirs of HIV represent a major barrier to cure efforts. One promising approach for eradicating these reservoirs is the concept of kick-and-kill, which seeks to reactivate latent proviruses using pharmaceutical agents, thereby exposing them to elimination by immune effectors. This strategy has seen broad success in many in vitro primary cell and cell line models of HIV latency, but clinical results have largely been disappointing. New evidence points to a wide rift in characteristics between the latent reservoirs generated in vitro, as compared to latent reservoirs that arise naturally and persist for long time periods in ART-suppressed individuals. These data indicate a need for further testing of kick-and-kill strategies in ex vivo settings to establish a proof-of-concept. Here, we develop a novel HIV eradication (HIVE) assay, specifically for evaluating the efficacy of various kick-and-kill approaches on resting CD4+ T cells directly ex vivo from ART-suppressed individuals. Using this assay, we first demonstrate that cells harboring latent, replication competent proviruses exhibit an inherent resistance to CD8+ T cell elimination, while cells harboring defective proviruses do not. We show that this resistance is not a result of immune escape, CD8+ T cell dysfunction/lack of cytotoxicity, nor a lack of latency reversal. We next explore mechanisms to overcome this resistance to killing, and find that cells may be sensitized to apoptosis through treatment with the Bcl-2 inhibitor ‘ABT-199’, rendering them vulnerable to immune effectors. These studies provide evidence for the new approach of ‘prime, kick, and kill’, for reservoir eradication.
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