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

Carolina Garrido,Adam M Spivak,Edward Barker,Mary Ann Checkley,Natalia Soriano-Sarabia,Jonathan Karn,Vicente Planelles,David M Margolis

doi:10.3389/fimmu.2016.00356

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.

Highlights

The recent description of an HIV-1 infected individual who experienced a sterilizing cure [1], without evidence of replication-competent virus in vivo, and others in whom early antiretroviral therapy (ART) resulted in undetectable viremia and maintenance of immune competence despite the cessation of ART [2], has given rise to a variety of experimental approaches to induce cure or drug-free remission of HIV-1 infection
Viral inhibition capacity of natural killer (NK) cells was tested in autologous cell systems, using NK and CD4+ T cells from the same donor
Results obtained from latency reversing agents (LRA)-treated NK cell conditions were normalized to viral inhibition observed in the untreated NK cell condition

Summary

Introduction

The recent description of an HIV-1 infected individual who experienced a sterilizing cure [1], without evidence of replication-competent virus in vivo, and others in whom early antiretroviral therapy (ART) resulted in undetectable viremia and maintenance of immune competence despite the cessation of ART (a functional cure) [2], has given rise to a variety of experimental approaches to induce cure or drug-free remission of HIV-1 infection. PKC agonists induce latent viral expression though NF-κB signaling [10] Members of these two LRA classes have demonstrated efficacy in inducing HIV-1 expression in cells from patients on ART in vivo and in vitro [9, 11,12,13,14,15,16]. As both histone deacetylation and signaling through NF-κB may impact the function of diverse cell populations, the effect of LRAs beyond latently infected cells must be carefully evaluated

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