Cargando…

Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation

Human Immunodeficiency Virus-1 (HIV) remains a global health challenge due to the latent HIV reservoirs in people living with HIV (PLWH). Dormant yet replication competent HIV harbored in the resting CD4+ T cells cannot be purged by antiretroviral therapy (ART) alone. One approach of HIV cure is the...

Descripción completa

Detalles Bibliográficos
Autores principales: Wong, Lilly M., Li, Dajiang, Tang, Yuyang, Méndez-Lagares, Gema, Thompson, George R., Hartigan-O’Connor, Dennis J., Dandekar, Satya, Jiang, Guochun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960990/
https://www.ncbi.nlm.nih.gov/pubmed/35359743
http://dx.doi.org/10.3389/fmicb.2022.836831
_version_ 1784677501344153600
author Wong, Lilly M.
Li, Dajiang
Tang, Yuyang
Méndez-Lagares, Gema
Thompson, George R.
Hartigan-O’Connor, Dennis J.
Dandekar, Satya
Jiang, Guochun
author_facet Wong, Lilly M.
Li, Dajiang
Tang, Yuyang
Méndez-Lagares, Gema
Thompson, George R.
Hartigan-O’Connor, Dennis J.
Dandekar, Satya
Jiang, Guochun
author_sort Wong, Lilly M.
collection PubMed
description Human Immunodeficiency Virus-1 (HIV) remains a global health challenge due to the latent HIV reservoirs in people living with HIV (PLWH). Dormant yet replication competent HIV harbored in the resting CD4+ T cells cannot be purged by antiretroviral therapy (ART) alone. One approach of HIV cure is the “Kick and Kill” strategy where latency reversal agents (LRAs) have been implemented to disrupt latent HIV, expecting to eradicate HIV reservoirs by viral cytopathic effect or immune-mediated clearance. Protein Kinase C agonists (PKCa), a family of LRAs, have demonstrated the ability to disrupt latent HIV to an extent. However, the toxicity of PKCa remains a concern in vivo. Early growth response protein 1 (EGR1) is a downstream target of PKCa during latency reversal. Here, we show that PKCa induces EGR1 which directly drives Tat-dependent HIV transcription. Resveratrol, a natural phytoalexin found in grapes and various plants, induces Egr1 expression and disrupts latent HIV in several HIV latency models in vitro and in CD4+ T cells isolated from ART-suppressed PLWH ex vivo. In the primary CD4+ T cells, resveratrol does not induce immune activation at the dosage that it reverses latency, indicating that targeting EGR1 may be able to reverse latency and bypass PKCa-induced immune activation.
format Online
Article
Text
id pubmed-8960990
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-89609902022-03-30 Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation Wong, Lilly M. Li, Dajiang Tang, Yuyang Méndez-Lagares, Gema Thompson, George R. Hartigan-O’Connor, Dennis J. Dandekar, Satya Jiang, Guochun Front Microbiol Microbiology Human Immunodeficiency Virus-1 (HIV) remains a global health challenge due to the latent HIV reservoirs in people living with HIV (PLWH). Dormant yet replication competent HIV harbored in the resting CD4+ T cells cannot be purged by antiretroviral therapy (ART) alone. One approach of HIV cure is the “Kick and Kill” strategy where latency reversal agents (LRAs) have been implemented to disrupt latent HIV, expecting to eradicate HIV reservoirs by viral cytopathic effect or immune-mediated clearance. Protein Kinase C agonists (PKCa), a family of LRAs, have demonstrated the ability to disrupt latent HIV to an extent. However, the toxicity of PKCa remains a concern in vivo. Early growth response protein 1 (EGR1) is a downstream target of PKCa during latency reversal. Here, we show that PKCa induces EGR1 which directly drives Tat-dependent HIV transcription. Resveratrol, a natural phytoalexin found in grapes and various plants, induces Egr1 expression and disrupts latent HIV in several HIV latency models in vitro and in CD4+ T cells isolated from ART-suppressed PLWH ex vivo. In the primary CD4+ T cells, resveratrol does not induce immune activation at the dosage that it reverses latency, indicating that targeting EGR1 may be able to reverse latency and bypass PKCa-induced immune activation. Frontiers Media S.A. 2022-03-10 /pmc/articles/PMC8960990/ /pubmed/35359743 http://dx.doi.org/10.3389/fmicb.2022.836831 Text en Copyright © 2022 Wong, Li, Tang, Méndez-Lagares, Thompson, Hartigan-O’Connor, Dandekar and Jiang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Wong, Lilly M.
Li, Dajiang
Tang, Yuyang
Méndez-Lagares, Gema
Thompson, George R.
Hartigan-O’Connor, Dennis J.
Dandekar, Satya
Jiang, Guochun
Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation
title Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation
title_full Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation
title_fullStr Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation
title_full_unstemmed Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation
title_short Human Immunodeficiency Virus-1 Latency Reversal via the Induction of Early Growth Response Protein 1 to Bypass Protein Kinase C Agonist-Associated Immune Activation
title_sort human immunodeficiency virus-1 latency reversal via the induction of early growth response protein 1 to bypass protein kinase c agonist-associated immune activation
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960990/
https://www.ncbi.nlm.nih.gov/pubmed/35359743
http://dx.doi.org/10.3389/fmicb.2022.836831
work_keys_str_mv AT wonglillym humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT lidajiang humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT tangyuyang humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT mendezlagaresgema humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT thompsongeorger humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT hartiganoconnordennisj humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT dandekarsatya humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation
AT jiangguochun humanimmunodeficiencyvirus1latencyreversalviatheinductionofearlygrowthresponseprotein1tobypassproteinkinasecagonistassociatedimmuneactivation