دورية أكاديمية
Pharmacological Inhibition of PPARy Boosts HIV Reactivation and Th17 Effector Functions, while Preventing Progeny Virion Release and de novo Infection
| العنوان: | Pharmacological Inhibition of PPARy Boosts HIV Reactivation and Th17 Effector Functions, while Preventing Progeny Virion Release and de novo Infection |
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| المؤلفون: | Delphine Planas, Augustine Fert, Yuwei Zhang, Jean-Philippe Goulet, Jonathan Richard, Andrés Finzi, Maria Julia Ruiz, Laurence Raymond Marchand, Debashree Chatterjee, Huicheng Chen, Tomas Raul Wiche Salinas, Annie Gosselin, Eric A. Cohen, Jean-Pierre Routy, Nicolas Chomont, Petronela Ancuta |
| المصدر: | Pathogens and Immunity, Vol 5, Iss 1, Pp 177-239 (2020) |
| بيانات النشر: | Case Western Reserve University, 2020. |
| سنة النشر: | 2020 |
| المجموعة: | LCC:Pathology LCC:Immunologic diseases. Allergy |
| مصطلحات موضوعية: | hiv-1, art, cd4+ t cells, th17, ppary, il-21, Pathology, RB1-214, Immunologic diseases. Allergy, RC581-607 |
| الوصف: | The frequency and functions of Th17-polarized CCR6+RORyt+CD4+ T cells are rapidly compromised upon HIV infection and are not restored with long-term viral suppressive antiretroviral therapy (ART). In line with this, Th17 cells represent selective HIV-1 infection targets mainly at mucosal sites, with long-lived Th17 subsets carrying replication-competent HIV-DNA during ART. Therefore, novel Th17-specific therapeutic interventions are needed as a supplement of ART to reach the goal of HIV remission/cure. Th17 cells express high levels of peroxisome proliferator-activated receptor gamma (PPARy), a transcriptional factor that represses the transcription of the HIV provirus and the rorc gene, which encodes for the Th17-specific master regulator RORyt/RORC2. Thus, we hypothesized that the pharmacological inhibition of PPARy will facilitate HIV reservoir reactivation while enhancing Th17 effector functions. Consistent with this prediction, the PPARy antagonist T0070907 significantly increased HIV transcription (cell-associated HIV-RNA) and RORyt-mediated Th17 effector functions (IL-17A). Unexpectedly, the PPARy antagonism limited HIV outgrowth from cells of ART-treated people living with HIV (PLWH), as well as HIV replication in vitro. Mechanistically, PPARy inhibition in CCR6+CD4+ T cells induced the upregulation of transcripts linked to Th17-polarisation (RORyt, STAT3, BCL6 IL-17A/F, IL-21) and HIV transcription (NCOA1-3, CDK9, HTATIP2). Interestingly, several transcripts involved in HIV-restriction were upregulated (Caveolin-1, TRIM22, TRIM5α, BST2, miR-29), whereas HIV permissiveness transcripts were downregulated (CCR5, furin), consistent with the decrease in HIV outgrowth/replication. Finally, PPARy inhibition increased intracellular HIV-p24 expression and prevented BST-2 downregulation on infected T cells, suggesting that progeny virion release is restricted by BST-2-dependent mechanisms. These results provide a strong rationale for considering PPARy antagonism as a novel strategy for HIV-reservoir purging and restoring Th17-mediated mucosal immunity in ART-treated PLWH. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2469-2964 |
| العلاقة: | https://paijournal.com/index.php/paijournal/article/view/348Test; https://doaj.org/toc/2469-2964Test |
| DOI: | 10.20411/pai.v5i1.348 |
| الوصول الحر: | https://doaj.org/article/9a7a563c0479417c8f5e6fd508f2099bTest |
| رقم الانضمام: | edsdoj.9a7a563c0479417c8f5e6fd508f2099b |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 24692964 |
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| DOI: | 10.20411/pai.v5i1.348 |