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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8541327 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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