Latency-Reversing Agents Induce Differential Responses in Distinct Memory CD4 T Cell Subsets in Individuals on Antiretroviral Therapy

Marion Pardons,Rémi Fromentin,Amélie Pagliuzza,Jean-Pierre Routy,Nicolas Chomont

doi:10.1016/j.celrep.2019.10.101

Abstract

Latent proviruses persist in central (TCM), transitional (TTM), and effector (TEM) memory cells. We measured the levels of cellular factors involved in HIV gene expression in these subsets. The highest levels of acetylated H4, active nuclear factor κB (NF-κB), and active positive transcription elongation factor b (P-TEFb) were measured in TEM, TCM, and TTM cells, respectively. Vorinostat and romidepsin display opposite abilities to induce H4 acetylation across subsets. Protein kinase C (PKC) agonists are more efficient at inducing NF-κB phosphorylation in TCM cells but more potent at activating PTEF-b in the TEM subset. We selected the most efficient latency-reversing agents (LRAs) and measured their ability to reverse latency in each subset. While ingenol alone has modest activities in the three subsets, its combination with a histone deacetylase inhibitor (HDACi) dramatically increases latency reversal in TCM cells. Altogether, these results indicate that cellular HIV reservoirs are differentially responsive to common LRAs and suggest that combination of compounds will be required to achieve latency reversal in all subsets.

Highlights

More than 30 years after its discovery, there is still no cure for HIV infection, and more than 35 million people live with the virus worldwide
Antiretroviral therapy (ART) drastically reduces plasma viremia and improves the quality of life of people living with HIV (Palella et al, 1998), it does not eradicate the virus from the body (Palmer et al, 2008) and causes rebound after antiretroviral therapy (ART) cessation in all but exceptional cases (Saez-Cirion et al, 2013)
HDAC Inhibitors Display Variable Activities in Subsets of Memory CD4 T Cells It is well established that histone deacetylation contributes to HIV latency in primary CD4 T cells (Coull et al, 2000; Imai and Okamoto, 2006; Jiang et al, 2007; Marban et al, 2007; Tyagi and Karn, 2007; Williams et al, 2006)

Summary

Introduction

More than 30 years after its discovery, there is still no cure for HIV infection, and more than 35 million people live with the virus worldwide. A variety of LRAs have been tested for their ability to reactivate HIV expression in vitro, ex vivo, and in vivo (Archin et al, 2009; Bartholomeeusen et al, 2012, 2013; Budhiraja and Rice, 2013; Bullen et al, 2014; Fujinaga et al, 2015; Jiang et al, 2015; Spina et al, 2013; Tsai et al, 2016; Wei et al, 2014; Williams et al, 2004) Even though these LRAs induced increases in cell-associated HIV RNA or in plasma viremia in vivo, none of these clinical interventions led to a significant reduction in the size of the HIV reservoir (Archin et al, 2008, 2010, 2012, 2017; Delagreverie et al, 2016; Elliott et al, 2014; Gutierrez et al, 2016; Rasmussen et al, 2014; Routy et al, 2012; Sagot-Lerolle et al, 2008; Siliciano et al, 2007; Søgaard et al, 2015). Studies assessing the impact of LRAs combinations on viral reactivation ex vivo should facilitate the implementation of combinatorial interventions in clinical trials

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