Targeted deletion in the beta20-beta21 loop of HIV envelope glycoprotein gp120 exposes the CD4 binding site for antibody binding.
Different isolates of HIV-1 are known to vary in antibody binding and sensitivity to neutralization. In response to selective pressure, the virus may conceal important neutralizing determinants, such as the CD4 binding site on gp120, through steric hindrance or conformational masking. The 3D structure of gp120 shows five loop structures that surround the CD4 binding site (CD4BS) and may restrict antibody access to the site. We have generated gp120 mutants lacking each of these loops and characterized them with a panel of monoclonal antibodies, including b12 and F105. A targeted deletion in the beta20-beta21 loop resulted in gp120 with enhanced binding of both monoclonals. Enhancement of b12 binding suggests reduced steric hindrance, since the antibody is relatively insensitive to conformation. Enhanced binding of F105, which depends strongly on the protein conformation, suggests that the mutation may allow gp120 to move more freely into the liganded form. The same viral strategies that limit antibody binding may also inhibit antibody induction. Modified forms of gp120, in which the CD4 binding site is more exposed and accessible to antibodies, could provide novel immunogens for eliciting antibodies to this broadly shared neutralizing determinant.
Laboratory of Immunoregulation, DVP, Office of Vaccine Research and Review, Center for Biologics, FDA, Bldg 29, Room 523, NIH Campus, Bethesda, MD 20892, USA. ira.berkower@fda.hhs.gov
Ira
I
Berkower
Chiraag
C
Patel
Yisheng
Y
Ni
Konstantin
K
Virnik
Zhexin
Z
Xiang
Angelo
A
Spadaccini
D000915:Antibody Affinity; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000276:immunology*; D017353:Gene Deletion; D015483:HIV Antibodies / Q000276:immunology* / Q000378:metabolism; D015488:HIV Antigens / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology
D015704:CD4 Antigens; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments