title: CD8+ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles.
abstract: The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P = 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8(+) T cell responses against Gag and enhanced ability of CD8(+) T cells to suppress viral replication ex vivo In some cases, loss of virological control was associated with reduction in the total breadth of CD8(+) T cell responses in the absence of differences in HIV-1-specific CD8(+) T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8(+) T cell responses characterized by reduced ability to suppress viral replication ex vivo These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8(+) T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8(+) T cell-independent mechanisms.
  
  
  
  Host mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8(+) T cells that targeted the Gag protein, and CD8(+) T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8(+) T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine.
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Catherine K
authors.initials: CK
authors.lastname: Koofhethile
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
authors.forename: Zaza M
authors.initials: ZM
authors.lastname: Ndhlovu
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Christina
authors.initials: C
authors.lastname: Thobakgale-Tshabalala
authors.affiliation: AIDS Research Institute IrsiCaixa, Hospital Universitari Germans TriasiPujol, Barcelona, Spain.
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Nasreen
authors.initials: N
authors.lastname: Ismail
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Zenele
authors.initials: Z
authors.lastname: Mncube
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Lungile
authors.initials: L
authors.lastname: Mkhize
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Mary
authors.initials: M
authors.lastname: van der Stok
authors.affiliation: Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
authors.forename: Nonhlanhla
authors.initials: N
authors.lastname: Yende
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.|Department of Paediatrics, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip J R
authors.initials: PJR
authors.lastname: Goulder
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa Ndungu@ukzn.ac.za.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.|KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), University of KwaZulu-Natal, Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008137:Longitudinal Studies; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019562:Viral Load; D014766:Viremia / Q000188:drug therapy / Q000276:immunology*; D014779:Virus Replication
chemical_list: D015395:Histocompatibility Antigens Class I