title: Changes in paracrine interleukin-2 requirement, CCR7 expression, frequency, and cytokine secretion of human immunodeficiency virus-specific CD4+ T cells are a consequence of antigen load.
abstract: Virus-specific CD4+ T-cell responses are thought to be required for the induction and maintenance of many effective CD8+ T-cell and B-cell immune responses in experimental animals and humans. Although the presence of human immunodeficiency virus (HIV)-specific CD4+ T cells has been documented in patients at all stages of HIV infection, many fundamental questions regarding their frequency and function remain. A 10-color, 12-parameter flow cytometric panel was utilized to examine the frequency, memory phenotype (CD27, CCR7, and CD45RA), and cytokine production (interleukin-2 [IL-2], gamma interferon, and tumor necrosis factor alpha) of CD4+ T cells specific for HIV antigens as well as for adenovirus, Epstein-Barr virus (EBV), influenza H1N1 virus, influenza H3N2 virus, cytomegalovirus, varicella-zoster virus (VZV), and tetanus toxoid in normal controls, long-term nonprogressors (LTNP), and HIV-infected patients with progressive disease on or off therapy. The HIV-specific CD4+ T-cell responses in LTNP and patients on therapy were similar in frequency, phenotype, and cytokine production to responses directed against adenovirus, EBV, influenza virus, and VZV. HIV-specific CD4+ T cells from patients off antiretroviral therapy demonstrated a shift towards a CCR7(-) CD45RA(-) phenotype and a reduced percentage of IL-2-producing cells. The alterations in cytokine production during HIV viremia were found to be intrinsic to the HIV-specific CD4+ T cells and caused a requirement for IL-2 supplied exogenously for proliferation to occur. These observations suggest that many previously described changes in HIV-specific CD4+ T-cell function and phenotype are a consequence of high levels of antigen in viremic patients. In addition, defects in function and phenotype of HIV-specific CD4+ T cells are not readily discernible in the context of antiretroviral therapy but rather are similar to responses to other viruses.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive, MSC 1876, Bethesda, MD 20892-1876, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Tilton
authors.forename: Marlise R
authors.initials: MR
authors.lastname: Luskin
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Johnson
authors.forename: Maura
authors.initials: M
authors.lastname: Manion
authors.forename: Claire W
authors.initials: CW
authors.lastname: Hallahan
authors.forename: Julia A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Mary
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Richard T
authors.initials: RT
authors.lastname: Davey
authors.forename: Mark
authors.initials: M
authors.lastname: Connors
mesh_terms: D000256:Adenoviridae / Q000276:immunology; D000998:Antiviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism*; D003587:Cytomegalovirus / Q000276:immunology; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000276:immunology*; D014645:Herpesvirus 3, Human / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000032:analysis; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology* / Q000378:metabolism; D013745:Tetanus Toxoid / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014766:Viremia
chemical_list: D000998:Antiviral Agents; C515370:CCR7 protein, human; D016207:Cytokines; D007376:Interleukin-2; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D013745:Tetanus Toxoid; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens