title: Impaired Upregulation of the Costimulatory Molecules, CD27 and CD28, on CD4+T Cells from HIV Patients Receiving ART Is Associated with Poor Proliferative Responses.
abstract: HIV patients beginning antiretroviral therapy (ART) with advanced immunodeficiency often retain low CD4+T cell counts despite virological control. We examined proliferative responses and upregulation of costimulatory molecules, following anti-CD3 stimulation, in HIV patients with persistent CD4+T cell deficiency on ART. Aviremic HIV patients with nadir CD4+T cell counts <100 cells/μL and who had received ART for a median time of 7 (range 1-11) years were categorized into those achieving low (<350 cells/μL; n = 13) or normal (>500 cells/μL; n = 20) CD4+T cell counts. Ten healthy controls were also recruited. CD4+T cell proliferation (Ki67) and upregulation of costimulatory molecules (CD27 and CD28) after anti-CD3 stimulation were assessed by flow cytometry. Results were related to proportions of CD4+T cells expressing markers of T cell senescence (CD57), activation (HLA-DR), and apoptotic potential (Fas). Expression of CD27 and/or CD28 on uncultured CD4+T cells was similar in patients with normal CD4+T cell counts and healthy controls, but lower in patients with low CD4+T cell counts. Proportions of CD4+T cells expressing CD27 and/or CD28 correlated inversely with CD4+T cell expression of CD57, HLA-DR, and Fas. After anti-CD3 stimulation, induction of CD27hiCD28hiexpression was independent of CD4+T cell counts, but lower in HIV patients than in healthy controls. Induction of CD27hiCD28hiexpression correlated with induction of Ki67 expression in total, naïve, and CD31+naïve CD4+T cells from patients. In HIV patients responding to ART, impaired induction of CD27 and CD28 on CD4+T cells after stimulation with anti-CD3 is associated with poor proliferative responses as well as greater CD4+T cell activation and immunosenescence.
authors.affiliation: 1 School of Pathology and Laboratory Medicine, University of Western Australia , Perth, Australia .
authors.forename: Sara
authors.initials: S
authors.lastname: Tanaskovic
authors.affiliation: 2 School of Biomedical Science, Curtin University of Technology , Perth, Australia .
authors.forename: Patricia
authors.initials: P
authors.lastname: Price
authors.affiliation: 1 School of Pathology and Laboratory Medicine, University of Western Australia , Perth, Australia .|3 Department of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine , Perth, Australia .
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.affiliation: 1 School of Pathology and Laboratory Medicine, University of Western Australia , Perth, Australia .
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernandez
mesh_terms: D000328:Adult; D000368:Aged; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000032:analysis*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis*; D015854:Up-Regulation
chemical_list: D044966:Anti-Retroviral Agents; D018106:CD28 Antigens; D019394:Ki-67 Antigen; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: CD27/CD28 costimulatory molecules; CD4+ T-cell; HIV; anti-CD3 stimulation; immune activation; proliferation