title: High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted Gag-derived epitopes associated with relative HIV control.
abstract: Virus-specific cytotoxic T lymphocytes (CTL) with high levels of functional avidity have been associated with viral clearance in hepatitis C virus infection and with enhanced antiviral protective immunity in animal models. However, the role of functional avidity as a determinant of HIV-specific CTL efficacy remains to be assessed. Here we measured the functional avidities of HIV-specific CTL responses targeting 20 different, optimally defined CTL epitopes restricted by 13 different HLA class I alleles in a cohort comprising 44 HIV controllers and 68 HIV noncontrollers. Responses restricted by HLA-B alleles and responses targeting epitopes located in HIV Gag exhibited significantly higher functional avidities than responses restricted by HLA-A or HLA-C molecules (P = 0.0003) or responses targeting epitopes outside Gag (P < 0.0001). The functional avidities of Gag-specific and HLA-B-restricted responses were higher in HIV controllers than in noncontrollers (P = 0.014 and P = 0.018) and were not restored in HIV noncontrollers initiating antiretroviral therapy. T-cell receptor (TCR) analyses revealed narrower TCR repertoires in higher-avidity CTL populations, which were dominated by public TCR sequences in HIV controllers. Together, these data link the presence of high-avidity Gag-specific and HLA-B-restricted CTL responses with viral suppression in vivo and provide new insights into the immune parameters that mediate spontaneous control of HIV infection.
authors.affiliation: AIDS Research Institute, Fundació IrsiCaixa-HIVACAT, Hospital Universitari Germans Trias i Pujol, Ctra. del Canyet s/n, 08916 Badalona, Barcelona, Catalonia, Spain.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Berger
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Beatriz
authors.initials: B
authors.lastname: Mothe
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.forename: Kari L
authors.initials: KL
authors.lastname: Hartman
authors.forename: Leah M
authors.initials: LM
authors.lastname: Henry
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Laura E
authors.initials: LE
authors.lastname: Ruff
authors.forename: Vanessa
authors.initials: V
authors.lastname: Venturi
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
mesh_terms: D015331:Cohort Studies; D000939:Epitopes / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D020276:HIV Long-Term Survivors; D015234:HLA-A Antigens / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology; D006801:Humans; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D000939:Epitopes; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D011948:Receptors, Antigen, T-Cell; D054301:gag Gene Products, Human Immunodeficiency Virus