دورية أكاديمية
P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model.
| العنوان: | P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model. |
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| المؤلفون: | Soare AY; Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Durham ND; Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Division of Molecular Biology and Microbiology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA., Gopal R; Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Tweel B; Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Hoffman KW; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Brown JA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., O'Brien M; Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Bhardwaj N; Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Lim JK; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Chen BK; Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Swartz TH; Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA talia.swartz@mssm.edu. |
| المصدر: | Journal of virology [J Virol] 2018 Dec 10; Vol. 93 (1). Date of Electronic Publication: 2018 Dec 10 (Print Publication: 2019). |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Society For Microbiology Original Publication: Baltimore, American Society for Microbiology. |
| مواضيع طبية MeSH: | HIV Infections/*immunology , HIV-1/*pathogenicity , Interleukin-10/*metabolism , Interleukin-1beta/*metabolism , Palatine Tonsil/*cytology , Purinergic P2X Receptor Antagonists/*pharmacology, Benzenesulfonates/pharmacology ; Down-Regulation ; Gene Expression Regulation ; HIV Infections/drug therapy ; HIV-1/drug effects ; HIV-1/immunology ; Humans ; Models, Biological ; Palatine Tonsil/drug effects ; Palatine Tonsil/immunology ; Palatine Tonsil/virology ; Pyridines/pharmacology ; Tetrazoles/pharmacology ; Tissue Culture Techniques ; Virulence/drug effects ; Zidovudine/pharmacology |
| مستخلص: | HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An ex vivo human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation. IMPORTANCE Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted. (Copyright © 2018 American Society for Microbiology.) |
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| معلومات مُعتمدة: | DP1 DA028866 United States DA NIDA NIH HHS; K08 AI120806 United States AI NIAID NIH HHS; R01 AI074420 United States AI NIAID NIH HHS; K08 AI128068 United States AI NIAID NIH HHS |
| فهرسة مساهمة: | Keywords: IL-10; IL-1β; P2X; cytokines; human immunodeficiency virus; infectious disease; inflammasome; inflammation; purinergic; receptors |
| المشرفين على المادة: | 0 (3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine) 0 (4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate)) 0 (Benzenesulfonates) 0 (IL10 protein, human) 0 (IL1B protein, human) 0 (Interleukin-1beta) 0 (Purinergic P2X Receptor Antagonists) 0 (Pyridines) 0 (Tetrazoles) 130068-27-8 (Interleukin-10) 4B9XT59T7S (Zidovudine) |
| تواريخ الأحداث: | Date Created: 20181012 Date Completed: 20190930 Latest Revision: 20240214 |
| رمز التحديث: | 20240214 |
| مُعرف محوري في PubMed: | PMC6288349 |
| DOI: | 10.1128/JVI.01186-18 |
| PMID: | 30305360 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-5514 |
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| DOI: | 10.1128/JVI.01186-18 |