title: Comprehensive analysis of human immunodeficiency virus type 1-specific CD4 responses reveals marked immunodominance of gag and nef and the presence of broadly recognized peptides.
abstract: Increasing evidence suggests that human immunodeficiency virus type 1 (HIV-1)-specific CD4 T-cell responses contribute to effective immune control of HIV-1 infection. However, the breadths and specificities of these responses have not been defined. We screened fresh CD8-depleted peripheral blood mononuclear cells (PBMC) from 36 subjects at different stages of HIV-1 infection for virus-specific CD4 responses by gamma interferon enzyme-linked immunospot assay, using 410 overlapping peptides spanning all HIV-1 proteins (based on the clade B consensus sequence). HIV-1-specific CD4 responses were identified in 30 of the 36 individuals studied, with the strongest and broadest responses detected in persons treated in acute infection who underwent treatment interruption. In individuals with identified responses, the total number of recognized HIV-1 peptides ranged from 1 to 36 (median, 7) and the total magnitude of responses ranged from 80 to >14,600 (median, 990) spot-forming cells/10(6) CD8-depleted PBMC. Neither the total magnitude nor the number of responses correlated with viremia. The most frequent and robust responses were directed against epitopes within the Gag and Nef proteins. Peptides targeted by >/=25% of individuals were then tested for binding to a panel of common HLA-DR molecules. All bound broadly to at least four of the eight alleles tested, and two bound to all of the HLA-DR molecules studied. Fine mapping and HLA restriction of the responses against four of these peptides showed a combination of clustering of epitopes and promiscuous presentation of the same epitopes by different HLA class II alleles. These findings have implications for the design of immunotherapeutic strategies and for testing candidate HIV vaccines.
authors.affiliation: Partners AIDS Research Center and Infectious Disease Unit, Howard Hughes Medical Institute, Massachusetts General Hospital, and Division of AIDS, Boston, Massachusetts 02114, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Paul M
authors.initials: PM
authors.lastname: Bailey
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Bradford
authors.initials: B
authors.lastname: Wagner
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.forename: Mary N
authors.initials: MN
authors.lastname: Johnston
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cosimi
authors.forename: Marylyn M
authors.initials: MM
authors.lastname: Addo
authors.forename: Mathias
authors.initials: M
authors.lastname: Lichterfeld
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002675:Child, Preschool; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag / Q000276:immunology*; D015693:Gene Products, nef / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015693:Gene Products, nef; D006684:HLA-DR Antigens; D016056:Immunodominant Epitopes; D010455:Peptides; D054311:nef Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma