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

Abstract

Latent proviruses persist in central (T_CM), transitional (T_TM), and effector (T_EM) 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 T_EM, T_CM, and T_TM 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 T_CM cells but more potent at activating PTEF-b in the T_EM 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 T_CM 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.

Keywords: CD4 T cells; HIV reservoir; HIV-Flow; LRA; NF-κB; P-TEFb; histone acetylation; latency; latency-reversing agent; memory subsets.