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Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction.
Younes, Souheil-Antoine; Talla, Aarthi; Pereira Ribeiro, Susan; Saidakova, Evgeniya V; Korolevskaya, Larisa B; Shmagel, Konstantin V; Shive, Carey L; Freeman, Michael L; Panigrahi, Soumya; Zweig, Sophia; Balderas, Robert; Margolis, Leonid; Douek, Daniel C; Anthony, Donald D; Pandiyan, Pushpa; Cameron, Mark; Sieg, Scott F; Calabrese, Leonard H; Rodriguez, Benigno; Lederman, Michael M.
Afiliación
  • Younes SA; Division of Infectious Disease and.
  • Talla A; Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
  • Pereira Ribeiro S; Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
  • Saidakova EV; Institute of Ecology and Genetics of Microorganisms, Perm, Russia.
  • Korolevskaya LB; Institute of Ecology and Genetics of Microorganisms, Perm, Russia.
  • Shmagel KV; Institute of Ecology and Genetics of Microorganisms, Perm, Russia.
  • Shive CL; Division of Infectious Disease and.
  • Freeman ML; Divisions of Infectious and Rheumatic Diseases, University Hospitals Case Medical Center, The Cleveland VA Medical Center, and the Center for AIDS Research, Cleveland, Ohio, USA.
  • Panigrahi S; Division of Infectious Disease and.
  • Zweig S; Division of Infectious Disease and.
  • Balderas R; Division of Infectious Disease and.
  • Margolis L; Becton Dickinson, San Diego, California, USA.
  • Douek DC; National Institute of Child Health and Human Development and.
  • Anthony DD; Human Immunology Section, Vaccine Research Center, National Institutes of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.
  • Pandiyan P; Division of Infectious Disease and.
  • Cameron M; Divisions of Infectious and Rheumatic Diseases, University Hospitals Case Medical Center, The Cleveland VA Medical Center, and the Center for AIDS Research, Cleveland, Ohio, USA.
  • Sieg SF; School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
  • Calabrese LH; Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA.
  • Rodriguez B; Division of Infectious Disease and.
  • Lederman MM; Rheumatologic and Immunologic Disease, Cleveland Clinic, Cleveland, Ohio, USA.
J Clin Invest ; 128(11): 5083-5094, 2018 11 01.
Article en En | MEDLINE | ID: mdl-30320604
Immune nonresponder (INR) HIV-1-infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-ß activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1-infected subjects who fail to restore CD4+ T cells during antiretroviral therapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Infecciones por VIH / VIH-1 / Linfocitos T Reguladores / Interleucina-15 / Proteínas Mitocondriales / Proteínas de Unión al ADN / Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma / Mitocondrias Tipo de estudio: Clinical_trials Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción / Infecciones por VIH / VIH-1 / Linfocitos T Reguladores / Interleucina-15 / Proteínas Mitocondriales / Proteínas de Unión al ADN / Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma / Mitocondrias Tipo de estudio: Clinical_trials Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: J Clin Invest Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos