Mechanisms and efficacy of small molecule "latency promoting agents" to inhibit HIV reactivation ex vivo.
JCI Insight
; 2024 Aug 20.
Article
en En
| MEDLINE
| ID: mdl-39163135
ABSTRACT
HIV infection cannot be cured due to the persistence of a reservoir of latently infected cells. Furthermore, virally suppressed individuals experience chronic immune activation from ongoing low-level viral expression. Drugs that inhibit HIV transcription and/or reactivation of latent HIV have been proposed as a strategy to reduce HIV-associated immune activation and/or to achieve a functional cure. We evaluated 26 small molecules, both previously reported drugs and new drug candidates, for their ability to act as "latency promoting/silencing agents (LPAs)" that can reduce or prevent HIV expression after T cell activation. Using a panel of RT-ddPCR assays, we measured the progression through HIV transcription and pinpointed the step at which each of those drugs inhibited HIV transcription, with and without prior activation. While some drugs primarily inhibited one or two steps in HIV reactivation, other drugs (CDK inhibitors, splicing inhibitors, tanespimycin, and triptolide) inhibited multiple stages of HIV transcription and blocked the production of supernatant viral RNA. Dinaciclib, AZD4573, and pladienolide B also appeared to inhibit HIV splicing in unstimulated PBMC. By selecting drugs with known mechanisms of action, we specifically identified cellular factors and pathways that may be involved in regulation of HIV expression. These drugs/targets deserve further study in strategies aimed at reducing HIV-associated immune activation or achieving a functional cure.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
JCI Insight
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos