title: Neutralizing activity of antibodies to the V3 loop region of HIV-1 gp120 relative to their epitope fine specificity.
abstract: The V3 loop of HIV-1 gp120 is considered occluded on many primary viruses. However, virus sensitivity to neutralization by different V3 mAbs often varies, indicating that access to V3 is not restricted equally for all antibodies. Here, we have sought to gain a better understanding of these restrictions by determining the neutralizing activities of 7 V3 mAbs (19b, 39F, CO11, F2A3, F530, LA21, and LE311) against 15 subtype B primary isolates and relating these activities to the fine specificity of the mAbs. Not surprisingly, we found that most mAbs neutralized the same 2-3 viruses, with only mAb F530 able to neutralize 2 additional viruses not neutralized by the other mAbs. Epitope mapping revealed that positively-charged residues in or near the V3 stem are important for the binding of all the mAbs and that most mAbs seem to require the Pro residue that forms the GPGR beta hairpin turn in the V3 tip for binding. Based on the mapping, we determined that V3 sequence variation accounted for neutralization resistance of approximately half the viruses tested. Comparison of these results to those of select V3 mAbs with overall better neutralizing activities in the light of structural information illustrates how an antibody's mode of interaction with V3, driven by contact residue requirements, may restrict the antibody from accessing its epitope on different viruses. Based on the data we propose an angle of interaction with V3 that is less stringent on access for antibodies with cross-neutralizing activity compared to antibodies that neutralize relatively fewer viruses.
authors.affiliation: The Scripps Research Institute, Department of Immunology and Microbial Science, IMM2, 10550 North Torrey Pines Road La Jolla, CA 92037, USA. rpanto@scripps.edu
authors.forename: Ralph
authors.initials: R
authors.lastname: Pantophlet
authors.forename: Terri
authors.initials: T
authors.lastname: Wrin
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cavacini
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Burton
mesh_terms: D000409:Alanine / Q000032:analysis; D020816:Amino Acid Motifs / Q000276:immunology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1; D008958:Models, Molecular; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; D000409:Alanine