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Pharmacological suppression of glycogen synthase kinase-3 reactivates HIV-1 from latency via activating Wnt/β-catenin/TCF1 axis in CD4 + T cells.
- Source :
-
Emerging microbes & infections [Emerg Microbes Infect] 2022 Dec; Vol. 11 (1), pp. 391-405. - Publication Year :
- 2022
-
Abstract
- ABSTRACT HIV-1 latency posts a major obstacle for HIV-1 eradication. Currently, no desirable latency reversing agents (LRAs) have been implicated in the "Shock and Kill" strategy to mobilize the latently infected cells to be susceptible for clearance by immune responses. Identification of key cellular pathways that modulate HIV-1 latency helps to develop efficient LRAs. In this study, we demonstrate that the Wnt downstream β-catenin/TCF1 pathway is a crucial modulator for HIV-1 latency. The pharmacological activation of the β-catenin/TCF1 pathway with glycogen synthase kinase-3 (GSK3) inhibitors promoted transcription of HIV-1 proviral DNA and reactivated latency in CD4 <superscript>+</superscript> T cells; the GSK3 kinase inhibitor 6-bromoindirubin-3'-oxime (6-BIO)-induced HIV-1 reactivation was subsequently confirmed in resting CD4 <superscript>+</superscript> T cells from cART-suppressed patients and SIV-infected rhesus macaques. These findings advance our understanding of the mechanisms responsible for viral latency, and provide the potent LRA that can be further used in conjunction of immunotherapies to eradicate viral reservoirs.
- Subjects :
- Animals
CD4-Positive T-Lymphocytes immunology
Cell Line, Tumor
HIV-1 drug effects
HIV-1 genetics
HeLa Cells
Hepatocyte Nuclear Factor 1-alpha metabolism
Humans
Macaca mulatta
Transcription, Genetic drug effects
U937 Cells
Virus Activation genetics
Virus Latency genetics
Wnt Proteins metabolism
beta Catenin metabolism
CD4-Positive T-Lymphocytes virology
Glycogen Synthase Kinase 3 antagonists & inhibitors
HIV-1 growth & development
Indoles pharmacology
Oximes pharmacology
Virus Activation drug effects
Virus Latency drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2222-1751
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Emerging microbes & infections
- Publication Type :
- Academic Journal
- Accession number :
- 34985411
- Full Text :
- https://doi.org/10.1080/22221751.2022.2026198