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We have selected an HXB2 variant which can replicate in the presence of a neutralizing human serum. Sequencing of the gp120 region of the env gene from the variant and parental viruses identified a single amino acid substitution in the third conserved region of gp120 at residue 375 (AGT-->AAT, Ser-->Asn; designated 375 S/N). The escape mutant was found to be resistant to neutralization by soluble CD4 (sCD4) and four monoclonal antibodies (MAbs), 39.13g, 1.5e, G13, and 448, binding to epitopes overlapping that of the CD4 binding site (CD4 b.s.). Introduction of the 375 S/N mutation into HXB2 by site-directed mutagenesis confirmed that this mutation is responsible for the neutralization-resistant phenotype. Both sCD4 and three of the CD4 b.s. MAbs (39.13g, 1.5e, and G13) demonstrated reduced binding to the native 375 S/N mutant gp120. The ability to select for an escape variant resistant to multiple independent CD4 b.s. MAbs by a human serum confirms the reports that antibodies to the discontinuous CD4 b.s. are a major component of the group-specific neutralizing activity in human sera.

Original publication

DOI

10.1128/jvi.67.9.5216-5225.1993

Type

Journal article

Journal

Journal of virology

Publication Date

09/1993

Volume

67

Pages

5216 - 5225

Addresses

Chester Beatty Laboratories, Institute of Cancer Research, London, United Kingdom.

Keywords

Cell Line, Humans, HIV-1, Recombinant Proteins, HIV Envelope Protein gp120, Oligodeoxyribonucleotides, Antigens, CD, Antibodies, Monoclonal, Epitopes, Ligands, Neutralization Tests, Restriction Mapping, Cloning, Molecular, Transfection, Mutagenesis, Site-Directed, Binding Sites, Amino Acid Sequence, Base Sequence, Conserved Sequence, Point Mutation, Molecular Sequence Data, CD4 Antigens