HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

Abstract

In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection.

Interval dosing with the HDAC inhibitor vorinostat effectively reverses HIV latency

“…However, a full understanding of the optimal dosing schedule for romidepsin and its interaction with immunotherapies is still lacking. As we have previously shown for both CD8 and NK cell function in earlier VOR studies (19,33), in this study, we observed no significant effect of VOR on CD8 immune function after repeated dosing in vivo.…”

Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency Reversal Ex Vivo

“…However, a range of novel approaches to achieve HIV latency reversal are under study (37,38). Thus, in a similar way, future work must address the effect of novel latency-reversing agents (LRAs) on NK-mediated clearance, given that antigen presentation or ligand modulation might be altered by host-targeted LRAs (39). Of interest, there is evidence that HDAC inhibitor exposure upregulates the surface expression of ligands for activating receptors in NK cells (40,41).…”

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…Recent studies demonstrating diverse responses of infected cells to LRAs point to their weak effect (Archin et al, 2012;Spivak et al, 2014;Elliott et al, 2015) and highlight the diversity of determinants responsible for the reservoirs' heterogeneity that were demonstrated so far to be virus genetic background- (Norton et al, 2019), cell model- (Spina et al, 2013), cell type- (Baxter et al, 2016;Grau-Expósito et al, 2019;Kula et al, 2019), silencing mechanism- (Elliott et al, 2014;Yukl et al, 2018), tissue reservoir- (Elliott et al, 2014;Telwatte et al, 2018;Yukl et al, 2018), integration site- (Chen et al, 2017;Abner et al, 2018;Battivelli et al, 2018), patient- (Darcis et al, 2017;Yukl et al, 2018), and gender- (Das et al, 2018) specific. In addition, some studies demonstrate a heterogeneous effect of LRAs on NK cells (Garrido et al, 2016) and cytotoxic T-cell lymphocyte (Walker-Sperling et al, 2016) activity with conflicting observations, suggesting either an immunosuppressive effect or a reduced impact of LRA activity on cells sensing HIV-1 reactivation (Archin et al, 2012;Jones et al, 2014;Clutton et al, 2016;Walker-Sperling et al, 2016;Desimio et al, 2017Desimio et al, , 2018. Moreover, prolonged ART treatment is associated with a significant reduction in the frequency of HIV-1-specific CD8 + T-cells (Gray et al, 1999;Casazza et al, 2001).…”