title: IL-7-dependent STAT-5 activation and CD8+ T cell proliferation are impaired in HIV infection.
abstract: This study tests the hypothesis that IL-7 signaling and activity of CD8(+) T cells are impaired in HIV infection. IL-7 is necessary for optimal CTL activity and T cell survival and proliferation. Defects in IL-7R signaling may contribute to impaired activity of IL-7 observed in progressive HIV disease. A decreased proportion of CD8(+) T cells expressing the IL-7Rα chain (CD127) in progressive HIV disease would be expected to affect IL-7 activity. Alternatively, disease-associated defects of remaining CD8(+)CD127(+) T cells may influence IL-7 responsiveness. Therefore, the IL-7 responsiveness of CD8(+)CD127(+) T cells from HIV(-) and untreated or treated HIV(+) individuals was investigated. Blood was collected from HIV(-) and untreated or effectively treated HIV(+) (<50 viral copies/ml for >1 year) individuals, and CD8(+)CD127(+) T cells were isolated and cultured with IL-7. Indicators of IL-7 signaling (P-STAT5) and activity (Bcl-2 and proliferation) were evaluated by flow cytometry. Isolated CD8(+)CD127(+) T cells from untreated HIV(+) individuals expressed significantly less P-STAT5 in response to IL-7 compared with CD8(+)CD127(+) T cells from HIV(-) individuals. In effectively treated HIV(+) individuals, CD8(+)CD127(+) T cells also expressed significantly lower levels of P-STAT5 compared with HIV(-) individuals. IL-7-dependent proliferation of CD8(+)CD127(+) T cells from untreated HIV(+) individuals was similarly impaired. In contrast, IL-7-induced Bcl-2 expression was not impaired in CD8(+)CD127(+) T cells from HIV(+) individuals. These data demonstrate that IL-7/IL-7R dysfunction in HIV infection may contribute to IL-7-specific signaling defects. Decreased, IL-7-dependent activation of STAT5 and impaired proliferation may negatively impact the maintenance of CD8(+) T cell responsiveness in HIV infection.
authors.affiliation: Division of Infectious Diseases, Ottawa Hospital-General Campus, 501 Smyth Rd., Ottawa, Ontario, Canada.
authors.forename: Agatha
authors.initials: A
authors.lastname: Vranjkovic
authors.forename: Angela M
authors.initials: AM
authors.lastname: Crawley
authors.forename: Andrea
authors.initials: A
authors.lastname: Patey
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Angel
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003430:Cross-Sectional Studies; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor