The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation.

Ayaka Washizaki,Nadita P Wardani,Megumi Murata,Masayuki Kikumori,Yinpui Tang,Yohei Seki,Hirofumi Akari,Kazuhiro Irie,Weikeat Tan

doi:10.3390/v13102037

Ayaka Washizaki, Nadita P Wardani + Show 7 more

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https://doi.org/10.3390/v13102037

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Abstract

The presence of latent human immunodeficiency virus (HIV) reservoirs is a major obstacle to a cure. The “shock and kill” therapy is based on the concept that latent reservoirs in HIV carriers with antiretroviral therapy are reactivated by latency-reversing agents (LRAs), followed by elimination due to HIV-associated cell death or killing by virus-specific cytotoxic T lymphocytes. Protein kinase C (PKC) activators are considered robust LRAs as they efficiently reactivate latently infected HIV. However, various adverse events hamper the intervention trial of PKC activators as LRAs. We found in this study that a novel PKC activator, 10-Methyl-aplog-1 (10MA-1), combined with an inhibitor of bromodomain and extra-terminal domain motifs, JQ1, strongly and synergistically reactivated latently infected HIV. Notably, higher concentrations of 10MA-1 alone induced the predominant side effect, i.e., global T cell activation as defined by CD25 expression and pro-inflammatory cytokine production in primary CD4+ T lymphocytes; however, JQ1 efficiently suppressed the 10MA-1-induced side effect in a dose-dependent manner. Considering the reasonable accessibility and availability of 10MA-1 since the chemical synthesis of 10MA-1 requires fewer processes than that of bryostatin 1 or prostratin, our results suggest that the combination of 10MA-1 with JQ1 may be a promising pair of LRAs for the clinical application of the “shock and kill” therapy.

Highlights

Antiretroviral therapy (ART) development turns human immunodeficiency virus (HIV) infection to a manageable chronic disease
Combining a Protein kinase C (PKC) activator and a bromodomain and extraterminal domain motifs (BET) inhibitor synergistically reactivated HIV [4,13,28] and reduced global T cell activation and pro-inflammatory cytokine expression [28,29,30]. These results suggest that the combined use of a PKC activator and a BET inhibitor may overcome the safety issue of PKC activators as latency-reversing agents (LRAs)
To investigate whether 10MA-1 would reactivate latently infected HIV, Jurkat 1G5 was treated with LRAs, including prostratin, described previously [33]. 12Deoxyphorbol 13-phenylacetate (DPP), bryostatin 1, 10MA-1, JQ1, and suberoylanilide hydroxamic acid (SAHA). 10MA-1 induced luciferase activity in a dose-dependent manner, and the fold increase in relative luciferase unit (RLU) induced by 10MA-1 was comparable to that of prostratin and DPP

Summary

Introduction

Antiretroviral therapy (ART) development turns human immunodeficiency virus (HIV) infection to a manageable chronic disease. The “shock and kill” therapy is based on the concept that latency-reversing agents (LRAs) reactivate the latently infected HIV of ART controllers, followed by elimination due to HIV-associated cell death or killing by virus-specific cytotoxic T lymphocytes [1,2,3]. Abundant histone deacetylation and methylation occur in the proviral DNA of latently HIV-infected quiescent CD4+ T cells. This induces heterochromatic structure [5]. NF-κB activation and translocation into the nucleus lead to HIV reactivation in the latency [9,11]. Spina et al showed that PKC activators reactivated latently infected HIV through the NF-κB pathway from all latency models tested, whereas other classes of LRA did not. PKC activators are considered robust LRAs [11,19,20]

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