Permissive residues within the minimal epitopes of neutralizing monoclonal antibodies to the V3 loop of HIV-1.
Neutralizing monoclonal antibodies (mAb) specific for the third variable (V3) domain of gp120, the HIV-1 surface envelope protein, are mainly isolate specific. We have studied the composition and the permissivity of the minimal epitopes interacting with two of these, the 110-A and 19.26.4 mAb, which are strictly LAI isolate specific. Screening a hexapeptide phage library displayed on the surface of filamentous phage with the 110-A mAb has allowed selection of 49 phage sequences, permitting the definition of a consensus sequence. Based on this sequence, substituted synthetic peptides were prepared and used in binding assays. Our results show that both mAb interact with the same narrow region (316-320) of the V3 domain. The minimal epitope of the 110-A mAb was identified as a five amino acid sequence, Hy x R G p, where Hy represents any non-aromatic hydrophobic amino acid. By contrast, the minimal epitope of the 19.26.4 mAb was identified as x Q Pos G P, where Pos is any positively charged amino acid. Core residues of the epitope, critical for the binding to the mAb (written in uppercase letters), were set apart from permissive amino acid positions that tolerate substitutions (written in lowercase letters). Interestingly, the identified core residues Q2/317 (19.26.4 mAb) and R3/318 (110-A mAb) do not tolerate substitution and correspond to the QR insertion in the V3 domain, characteristic of the LAI isolate as compared to other isolates. This result may explain the strict isolate specificity of most anti-V3 LAI mAb. The two epitopes have totally different patterns of permissivity; thus, the effect of substitutions will differ depending on the mAb involved in the interaction. This suggests that the diversity of the antibody response is high enough to delay the emergence of HIV-1 variants resistant to neutralization by V3-specific antibodies.
Laisney
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IL
Laboratoire d'Immuno-pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Paris, France.
Benjamin
H
H
Gefter
M
M
Strosberg
A D
AD
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology; D000915:Antibody Affinity; D001483:Base Sequence; D001666:Binding Sites, Antibody; D001667:Binding, Competitive / Q000276:immunology; D016384:Consensus Sequence; D000939:Epitopes / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*
D000596:Amino Acids; D000911:Antibodies, Monoclonal; D000939:Epitopes; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments