The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function.

G Clutton,R Barnard,N Goonetilleke,K R Mollan,C L Gay,A Kashuba,J Kirchherr,P L Baldoni,J D Kuruc,D M Margolis,Y Xu,Kara Cox,W Newhard,M G Hudgens,N Archin

doi:10.1038/srep30749

Abstract

Despite the extraordinary success of HIV-1 antiretroviral therapy in prolonging life, infected individuals face lifelong therapy because of a reservoir of latently-infected cells that harbor replication competent virus. Recently, compounds have been identified that can reverse HIV-1 latency in vivo. These latency- reversing agents (LRAs) could make latently-infected cells vulnerable to clearance by immune cells, including cytolytic CD8+ T cells. We investigated the effects of two leading LRA classes on CD8+ T cell phenotype and function: the histone deacetylase inhibitors (HDACis) and protein kinase C modulators (PKCms). We observed that relative to HDACis, the PKCms induced much stronger T cell activation coupled with non-specific cytokine production and T cell proliferation. When examining antigen-specific CD8+ T cell function, all the LRAs except the HDACi Vorinostat reduced, but did not abolish, one or more measurements of CD8+ T cell function. Importantly, the extent and timing of these effects differed between LRAs. Panobinostat had detrimental effects within 10 hours of drug treatment, whereas the effects of the other LRAs were observed between 48 hours and 5 days. These observations suggest that scheduling of LRA and CD8+ T cell immunotherapy regimens may be critical for optimal clearance of the HIV-1 reservoir.

Highlights

Ability of CD8+T cells to respond to viral antigen
Jones et al reported that histone deacetylase inhibitors (HDACis) impaired HIV1-specific CD8+T cell responses in vitro[17], but this was not observed by Sung et al.[11], and in clinical studies there was no reduction in the frequency of cytokine-producing HIV-1-specific CD8+T cells following multiple doses of Vorinostat or Romidepsin[7,8]
We undertook a comprehensive analysis of the effects of clinically relevant doses and exposure periods to HDACis and protein kinase C modulators (PKCms) on T cell activation, cytokine production, production of cytotoxic effectors, and proliferation, using Peripheral blood mononuclear cells (PBMC) from HIV-1-infected participants durably suppressed on cART

Summary

Introduction

Ability of CD8+T cells to respond to viral antigen. Recently, Jones et al reported that HDACis impaired HIV1-specific CD8+T cell responses in vitro[17], but this was not observed by Sung et al.[11], and in clinical studies there was no reduction in the frequency of cytokine-producing HIV-1-specific CD8+T cells following multiple doses of Vorinostat or Romidepsin[7,8]. We undertook a comprehensive analysis of the effects of clinically relevant doses and exposure periods to HDACis and PKCms on T cell activation, cytokine production, production of cytotoxic effectors, and proliferation, using PBMC from HIV-1-infected participants durably suppressed on cART.

Results

Conclusion