In-vivo administration of histone deacetylase inhibitors does not impair natural killer cell function in HIV+ individuals.

Abstract

Histone deacetylase inhibitors (HDACi) have proven to induce HIV-RNA and antigen expression in resting CD4 T cells of antiretroviral therapy (ART)-treated HIV-infected individuals. However, to achieve viral eradication, immune clearance must follow latency reversal, and thus it is essential to understand the impact of latency reversal agents on immune function. Here we evaluate the impact of in-vivo administration of vorinostat (VOR) and panobinostat (PNB) during clinical trials on natural killer (NK) cell function and phenotype. Cryopreserved peripheral blood mononuclear cells from HIV-positive participants receiving VOR (NCT01319383) or PNB (NCT01680094) were selected to assess the impact of the drugs on cell composition, activation, NK cell phenotype (CD16, NKG2D, NKp30, NKp46 and DNAM-1), cytotoxic activity (CD107a), and interferon (IFN)-γ production. No impairment of NK cell function was observed during treatment with either VOR or PNB. An increase in the frequency of CD3CD56 NK cells was consistently observed. Interestingly, after VOR administration, NK cells increased expression of NKp46 and CD16, and showed improved degranulation and IFN-γ production capacity. Moreover, taking together VOR and PNB samples, HIV DNA levels in CD4 cells were negatively correlated with NK cell frequency and NK cell expression of CD16. In-vivo treatment with HDACi does not have measurable negative effects on NK cell function, with some evidence of improved function in vitro. These results have important implications for potential combinatorial approaches to target HIV reservoirs, suggesting that the use of HDACis as a latency reversal agent could be paired with interventions to enhance NK cell activity or recruitment.