Influence of disulfide-stabilized structure on the specificity of helper T-cell and antibody responses to HIV envelope glycoprotein gp120.
CD4(+) helper T cells specific for human immunodeficiency virus type 1 (HIV-1) are associated with control of viremia. Nevertheless, vaccines have had limited effectiveness thus far, in part because sequence variability and other structural features of the HIV envelope glycoprotein deflect the immune response. Previous studies indicated that CD4(+) T-cell epitope dominance is controlled by antigen three-dimensional structure through its influence on antigen processing and presentation. In this work, three disulfide bonds in the outer domain of gp120 were individually deleted in order to destabilize the local three-dimensional structure and enhance the presentation of nearby weakly immunogenic epitopes. However, upon immunization of groups of BALB/c mice, the CD4(+) T-cell response was broadly reduced for all three variants, and distinct epitope profiles emerged. For one variant, antibody titers were sharply increased, and the antibody exhibited significant CD4-blocking activity.
Mirano-Bascos
Denise
D
Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
Steede
N Kalaya
NK
Robinson
James E
JE
Landry
Samuel J
SJ
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002942:Circular Dichroism; D004220:Disulfides / Q000737:chemistry*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017434:Protein Structure, Tertiary; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D015704:CD4 Antigens; D004220:Disulfides; D018984:Epitopes, T-Lymphocyte; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120