| Autor: |
Tietjen I; The Wistar Institute, Philadelphia, Pennsylvania, USA.; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada., Schonhofer C; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada., Sciorillo A; The Wistar Institute, Philadelphia, Pennsylvania, USA., Naidu ME; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada., Haq Z; Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada., Kannan T; The Wistar Institute, Philadelphia, Pennsylvania, USA., Kossenkov AV; The Wistar Institute, Philadelphia, Pennsylvania, USA., Rivera-Ortiz J; The Wistar Institute, Philadelphia, Pennsylvania, USA., Mounzer K; Jonathan Lax Immune Disorders Treatment Center, Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, Pennsylvania, USA., Hart C; The Wistar Institute, Philadelphia, Pennsylvania, USA., Gyampoh K; The Wistar Institute, Philadelphia, Pennsylvania, USA., Yuan Z; The Wistar Institute, Philadelphia, Pennsylvania, USA., Beattie KD; Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, Queensland, Australia., Rali T; School of Natural and Physical Sciences, The University of Papua New Guinea, Port Moresby, Papua New Guinea., Shuda McGuire K; The Wistar Institute, Philadelphia, Pennsylvania, USA., Davis RA; Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, Queensland, Australia., Montaner LJ; The Wistar Institute, Philadelphia, Pennsylvania, USA. |
| Abstrakt: |
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. |
