Open AccessIdentification of celastrol as a novel HIV-1 latency reversal agent by an image-based screen
Author(s) -
Hongbing Liu,
Pei-Wen Hu,
Julien Dubrulle,
Fabio Stossi,
Bryan C. Nikolai,
Michael A. Mancini,
Andrew P. Rice
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0244771
Subject(s) - celastrol , jurkat cells , immune system , human immunodeficiency virus (hiv) , in vivo , biology , computational biology , immunology , t cell , genetics , apoptosis
Although current antiretroviral therapies (ART) are successful in controlling HIV-1 infection, a stable viral reservoir reactivates when ART is discontinued. Consequently, there is a major research effort to develop approaches to disrupt the latent viral reservoir and enhance the immune system’s ability to clear HIV-1. A number of small molecules, termed latency reversal agents (LRAs), have been identified which can reactivate latent HIV-1 in cell lines and patients’ cells ex vivo . However, clinical trials have suggested that combinations of LRAs will be required to efficiently reactivate HIV-1 in vivo , especially LRAs that act synergistically by functioning through distinct pathways. To identify novel LRAs, we used an image-based assay to screen a natural compound library for the ability to induce a low level of aggregation of resting primary CD4 + T cells from healthy donors. We identified celastrol as a novel LRA. Celastrol functions synergistically with other classes of LRA to reactivate latent HIV-1 in a Jurkat cell line, suggesting a novel mechanism in its LRA activity. Additionally, celastrol does not appear to activate resting CD4 + T cells at levels at which it can reactivate latent HIV-1. Celastrol appears to represent a novel class of LRAs and it therefore can serve as a lead compound for LRA development.