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

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...

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Autores principales: Washizaki, Ayaka, Murata, Megumi, Seki, Yohei, Kikumori, Masayuki, Tang, Yinpui, Tan, Weikeat, Wardani, Nadita P., Irie, Kazuhiro, Akari, Hirofumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541327/
https://www.ncbi.nlm.nih.gov/pubmed/34696466
http://dx.doi.org/10.3390/v13102037
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author Washizaki, Ayaka
Murata, Megumi
Seki, Yohei
Kikumori, Masayuki
Tang, Yinpui
Tan, Weikeat
Wardani, Nadita P.
Irie, Kazuhiro
Akari, Hirofumi
author_facet Washizaki, Ayaka
Murata, Megumi
Seki, Yohei
Kikumori, Masayuki
Tang, Yinpui
Tan, Weikeat
Wardani, Nadita P.
Irie, Kazuhiro
Akari, Hirofumi
author_sort Washizaki, Ayaka
collection PubMed
description 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.
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spelling pubmed-85413272021-10-24 The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation Washizaki, Ayaka Murata, Megumi Seki, Yohei Kikumori, Masayuki Tang, Yinpui Tan, Weikeat Wardani, Nadita P. Irie, Kazuhiro Akari, Hirofumi Viruses Article 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. MDPI 2021-10-09 /pmc/articles/PMC8541327/ /pubmed/34696466 http://dx.doi.org/10.3390/v13102037 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Washizaki, Ayaka
Murata, Megumi
Seki, Yohei
Kikumori, Masayuki
Tang, Yinpui
Tan, Weikeat
Wardani, Nadita P.
Irie, Kazuhiro
Akari, Hirofumi
The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation
title The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation
title_full The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation
title_fullStr The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation
title_full_unstemmed The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation
title_short The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation
title_sort novel pkc activator 10-methyl-aplog-1 combined with jq1 induced strong and synergistic hiv reactivation with tolerable global t cell activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541327/
https://www.ncbi.nlm.nih.gov/pubmed/34696466
http://dx.doi.org/10.3390/v13102037
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