Title |
The Natural Stilbenoid (–)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9
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Published in |
Antimicrobial Agents and Chemotherapy, March 2023
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DOI | 10.1128/aac.01600-22 |
Pubmed ID | |
Authors |
Ian Tietjen, Cole Schonhofer, Amanda Sciorillo, Maya E. Naidu, Zahra Haq, Toshitha Kannan, Andrew V. Kossenkov, Jocelyn Rivera-Ortiz, Karam Mounzer, Colin Hart, Kwasi Gyampoh, Zhe Yuan, Karren D. Beattie, Topul Rali, Kristy Shuda McGuire, Rohan A. Davis, Luis J. Montaner |
Abstract |
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 in vitro 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Australia | 2 | 14% |
India | 1 | 7% |
Paraguay | 1 | 7% |
United States | 1 | 7% |
France | 1 | 7% |
Unknown | 8 | 57% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 10 | 71% |
Scientists | 2 | 14% |
Practitioners (doctors, other healthcare professionals) | 2 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 8 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 1 | 13% |
Student > Ph. D. Student | 1 | 13% |
Professor > Associate Professor | 1 | 13% |
Student > Bachelor | 1 | 13% |
Unknown | 4 | 50% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 2 | 25% |
Immunology and Microbiology | 1 | 13% |
Unspecified | 1 | 13% |
Unknown | 4 | 50% |