title: Virological outcome after structured interruption of antiretroviral therapy for human immunodeficiency virus infection is associated with the functional profile of virus-specific CD8+ T cells.
abstract: A clear understanding of the antiviral effects of CD8(+) T cells in the context of chronic human immunodeficiency virus (HIV) infection is critical for the development of prophylactic vaccines and therapeutics designed to support T-cell-mediated immunity. However, defining the potential correlates of effective CD8(+) T-cell immunity has proven difficult; notably, comprehensive analyses have demonstrated that the size and shape of the CD8(+) T-cell response are not necessarily indicative of efficacy determined by measures of plasma viral load. Here, we conducted a detailed quantitative and qualitative analysis of CD8(+) T-cell responses to autologous virus in a cohort of six HIV-infected individuals with a history of structured interruption of antiretroviral therapy (ART) (SIT). The magnitude and breadth of the HIV-specific response did not, by themselves, explain the changes observed in plasma virus levels after the cessation of ART. Furthermore, mutational escape from targeted epitopes could not account for the differential virological outcomes in this cohort. However, the functionality of HIV-specific CD8(+) T-cell populations upon antigen encounter, determined by the simultaneous and independent measurement of five CD8(+) T-cell functions (degranulation and gamma interferon, macrophage inflammatory protein 1beta, tumor necrosis factor alpha, and interleukin-2 levels) reflected the emergent level of plasma virus, with multiple functions being elicited in those individuals with lower levels of viremia after SIT. These data show that the quality of the HIV-specific CD8(+) T-cell response, rather than the quantity, is associated with the dynamics of viral replication in the absence of ART and suggest that the effects of SIT can be assessed by measuring the functional profile of HIV-specific CD8(+) T cells.
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bldg. 10/Rm. 11B13, Bethesda, MD 20892, USA. mdaucher@niaid.nih.gov
authors.forename: Marybeth
authors.initials: M
authors.lastname: Daucher
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Laurie
authors.initials: L
authors.lastname: Lamoreaux
authors.forename: Julia A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Catherine
authors.initials: C
authors.lastname: Rehm
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nies-Kraske
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Urban
authors.forename: Christian
authors.initials: C
authors.lastname: Yoder
authors.forename: Diane
authors.initials: D
authors.lastname: Rock
authors.forename: Julie
authors.initials: J
authors.lastname: Gumkowski
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Mark R
authors.initials: MR
authors.lastname: Dybul
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015550:Cell Degranulation; D054407:Chemokine CCL4 / Q000096:biosynthesis; D015331:Cohort Studies; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008969:Molecular Sequence Data; D009154:Mutation; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019562:Viral Load; D014766:Viremia
chemical_list: D019380:Anti-HIV Agents; D054407:Chemokine CCL4; D000939:Epitopes; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma