title: Conformational instability governed by disulfide bonds partitions the dominant from subdominant helper T-cell responses specific for HIV-1 envelope glycoprotein gp120.
abstract: Most individuals infected with human immunodeficiency virus type 1 (HIV-1) generate a CD4(+) T-cell response that is dominated by a few epitopes. Immunodominance may be counterproductive because a broad CD4(+) T-cell response is associated with reduced viral load. Previous studies indicated that antigen three-dimensional structure controls antigen processing and presentation and therefore CD4(+) T-cell epitope dominance. Dominant epitopes occur adjacent to the V1-V2, V3, and V4 loops because proteolytic antigen processing in the loops promotes presentation of adjacent sequences. In this study, three gp120 (strain JR-FL) variants were constructed, in which deletions of single outer-domain disulfide bonds were expected to introduce local conformational flexibility and promote presentation of additional CD4(+) T-cell epitopes. Following mucosal immunization of C57BL/6 mice with wild-type or variant gp120 lacking the V3-flanking disulfide bond, the typical pattern of dominant epitopes was observed, suggesting that the disulfide bond posed no barrier to antigen presentation. In mice that lacked gamma interferon-inducible lysosomal thioreductase (GILT), proliferative responses to the typically dominant epitopes of gp120 were selectively depressed, and the dominance pattern was rearranged. Deletion of the V3-flanking disulfide bond or one of the V4-flanking disulfide bonds partially restored highly proliferative responses to the typically dominant epitopes. These results reveal an acute dependence of dominant CD4(+) T-cell responses on the native gp120 conformation.
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Hong-Nam P
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: N Kalaya
authors.initials: NK
authors.lastname: Steede
authors.affiliation: Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Electronic address: landry@tulane.edu.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Landry
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D004220:Disulfides / Q000737:chemistry*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D008810:Mice, Inbred C57BL; D010088:Oxidoreductases / Q000172:deficiency; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011487:Protein Conformation; D011489:Protein Denaturation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D004220:Disulfides; D018984:Epitopes, T-Lymphocyte; D015699:HIV Envelope Protein gp120; D016056:Immunodominant Epitopes; D010088:Oxidoreductases; C483811:Ifi30 protein, mouse; D050862:Oxidoreductases Acting on Sulfur Group Donors
keywords: Antigen presentation; Antigen processing; Cellular immune response; Disulfide; Lymphocyte; Protein conformation; T-helper; protein Denaturation