title: Emergence of polyfunctional CD8+ T cells after prolonged suppression of human immunodeficiency virus replication by antiretroviral therapy.
abstract: Progressive human immunodeficiency virus type 1 (HIV-1) infection is often associated with high plasma virus load (pVL) and impaired CD8(+) T-cell function; in contrast, CD8(+) T cells remain polyfunctional in long-term nonprogressors. However, it is still unclear whether CD8(+) T-cell dysfunction is the cause or the consequence of high pVLs. Here, we conducted a longitudinal functional and phenotypic analysis of virus-specific CD8(+) T cells in a cohort of patients with chronic HIV-1 infection. During the initiation and maintenance of successful antiretroviral therapy (ART), we assessed whether the level of pVL was associated with the degree of CD8(+) T-cell dysfunction. Under viremic conditions, HIV-specific CD8(+) T cells were dysfunctional with respect to cytokine secretion (gamma interferon, interleukin-2 [IL-2], and tumor necrosis factor alpha), and their phenotype suggested limited potential for proliferation. During ART, cytokine secretion by HIV-specific CD8(+) T cells was gradually restored, IL-7Ralpha and CD28 expression increased dramatically, and PD-1 levels declined. Thus, prolonged ART-induced reduction of viral replication and, hence, presumably antigen exposure in vivo, allows a significant functional restoration of CD8(+) T cells with the appearance of polyfunctional cells. These findings indicate that the level of pVL as a surrogate for antigen load has a dominant influence on the phenotypic and functional profile of virus-specific CD8(+) T cells.
authors.affiliation: Institute of Microbiology, ETH Hoenggerberg, HCI G401, Wolfgang Pauli Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Manuela
authors.initials: M
authors.lastname: Rehr
authors.forename: Julia
authors.initials: J
authors.lastname: Cahenzli
authors.forename: Anna
authors.initials: A
authors.lastname: Haas
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Milo
authors.initials: M
authors.lastname: Huber
authors.forename: Urs
authors.initials: U
authors.lastname: Karrer
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens; D007376:Interleukin-2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D020395:Receptors, Interleukin-7; D014409:Tumor Necrosis Factor-alpha; C415350:interleukin-7 receptor, alpha chain; D007371:Interferon-gamma