The Natural Stilbenoid (-)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9

Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to harbor replication-competent and transcriptionally active virus in infected cells, which in turn can lead to ongoing viral antigen production, chronic inflammation, and increased risk of age-relate...

Full description

Saved in:
Bibliographic Details
Published in:Antimicrobial agents and chemotherapy 2023-04, Vol.67 (4), p.e0160022
Main Authors: Tietjen, Ian, Schonhofer, Cole, Sciorillo, Amanda, Naidu, Maya E, Haq, Zahra, Kannan, Toshitha, Kossenkov, Andrew V, Rivera-Ortiz, Jocelyn, Mounzer, Karam, Hart, Colin, Gyampoh, Kwasi, Yuan, Zhe, Beattie, Karren D, Rali, Topul, Shuda McGuire, Kristy, Davis, Rohan A, Montaner, Luis J
Format: Article
Language:English
Subjects:
Antiviral Agents
Cyclin-Dependent Kinase 9 - metabolism
HIV Infections - metabolism
Humans
Leukocytes, Mononuclear - metabolism
NF-kappa B - genetics
NF-kappa B - metabolism
Protein Kinase C - genetics
RNA
Stilbenes - pharmacology
Virology
Virus Latency
Virus Replication
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to harbor replication-competent and transcriptionally active virus in infected cells, which in turn can lead to ongoing viral antigen production, chronic inflammation, and increased risk of age-related comorbidities. To identify new agents that may inhibit postintegration HIV beyond cART, we screened a library of 512 pure compounds derived from natural products and identified (-)-hopeaphenol as an inhibitor of HIV postintegration transcription at low to submicromolar concentrations without cytotoxicity. Using a combination of global RNA sequencing, plasmid-based reporter assays, and enzyme activity studies, we document that hopeaphenol inhibits protein kinase C (PKC)- and downstream NF-κB-dependent HIV transcription as well as a subset of PKC-dependent T-cell activation markers, including interleukin-2 (IL-2) cytokine and CD25 and HLA-DRB1 RNA production. In contrast, it does not substantially inhibit the early PKC-mediated T-cell activation marker CD69 production of IL-6 or NF-κB signaling induced by tumor necrosis factor alpha (TNF-α). We further show that hopeaphenol can inhibit cyclin-dependent kinase 9 (CDK9) enzymatic activity required for HIV transcription. Finally, it inhibits HIV replication in peripheral blood mononuclear cells (PBMCs) infected and dampens viral reactivation in CD4 cells from PLWH. Our study identifies hopeaphenol as a novel inhibitor that targets a subset of PKC-mediated T-cell activation pathways in addition to CDK9 to block HIV expression. Hopeaphenol-based therapies could complement current antiretroviral therapy otherwise not targeting cell-associated HIV RNA and residual antigen production in PLWH.
ISSN:0066-4804
1098-6596
1098-6596
DOI:10.1128/aac.01600-22