Potential Utility of Natural Killer Cells for Eliminating Cells Harboring Reactivated Latent HIV-1 Following the Removal of CD8+ T Cell-Mediated Pro-Latency Effect(s)

Abstract

An impediment to curing HIV-1 infection is the persistence of latently infected cells in ART-treated people living with HIV (PLWH). A key strategy for curing HIV-1 infection is to activate transcription and translation of latent virus using latency reversing agents (LRAs) and eliminate cells harboring reactivated virus via viral cytopathic effect or immune clearance. In this review, we provide an overview of available LRAs and their use in clinical trials. Furthermore, we describe recent data suggesting that CD8⁺ T cells promote HIV-1 latency in the context of ART, even in the presence of LRAs, which might at least partially explain the clinical inefficiency of previous "shock and kill" trials. Here, we propose a novel cure strategy called "unlock, shock, disarm, and kill". The general premise of this strategy is to shut down the pro-latency function(s) of CD8⁺ T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1.

Keywords: CD8+ T cells; HIV-1 cure; HIV-1 latency; NK cells.

Figure 1

HIV-1 latency reversing agents.

Figure 2

Viral dynamics following LRA administration and/or CD8⁺ T cell depletion in ART-treated SIV-infected rhesus macaques. The three graphs summarize the impact of (A) LRA administration, (B) CD8⁺ T cell depletion, or (C) combined CD8⁺ T cell depletion and LRA administration in ART-treated SIV-infected rhesus macaques. The graphs represent a summary of the general findings reported by McBrien et al. [22]. (A) LRA administration does not result in detectable viremia. (B,C) CD8⁺ T cell depletion results in detectable viremia, which is enhanced if LRA is administered concomitantly. Control of viremia is observed following CD8⁺ T cell repopulation. To facilitate a simple comparison of the three conditions, the graph depicted in (C) was prepared under the assumption that the administered LRA does not impact the dynamics of CD8⁺ T cell recovery post-depletion.

Figure 3

The “unlock, shock, disarm, and kill” strategy for HIV-1 eradication. The diagram depicts the “unlock, shock, disarm, and kill” strategy for HIV-1 eradication in the context of the ART-treated SIV-infected nonhuman primate (NHP) model. This multipronged strategy involves the sequential administration of four interventions. First, ART-treated SIV-infected NHP are administered an agent to inhibit the pro-latency effect(s) of CD8⁺ T cells, which facilitates the reactivation of latent virus in infected CD4⁺ T cells. Second, NHP are treated with pharmacological latency reversing agents (LRA), which further reactivate latent virus. Third, inhibitors of anti-apoptosis molecules are utilized to promote cell death in cells harboring reactivated latent virus. Finally, anti-viral antibodies, which recognize native trimeric envelope spikes, are administered to facilitate the recognition and elimination of cells harboring reactivated latent virus through antibody dependent cellular cytotoxicity (ADCC) mediated by effector cells such as natural killer (NK) cells.