title: Resistance of human immunodeficiency virus type 1 to neutralization by natural antisera occurs through single amino acid substitutions that cause changes in antibody binding at multiple sites.
abstract: The ability of human immunodeficiency virus type 1 (HIV-1) to replicate in the presence of strong immune responses to the virus may be due to its high mutation rate, which provides envelope gene variability for selection of neutralization-resistant variants. Understanding neutralization escape mechanisms is therefore important for the design of HIV-1 vaccines and our understanding of the disease process. In this report, we analyze mutations at amino acid positions 281 and 582 in the HIV-1 envelope, where substitutions confer resistance to broadly reactive neutralizing antisera from seropositive individuals. Neither of these mutations lies within an antibody-binding site, and therefore the mechanism of immune escape in both cases is by alteration of the shape of the envelope proteins. The conformation of the CD4-binding site is shown to be critical with regard to presentation of other discontinuous epitopes. From our analysis of the neutralization of these variants, we conclude that escape from polyclonal sera occurs through alterations at several different epitopes, generally resulting from single amino acid substitutions which influence envelope conformation. Experiments on a double mutant showed that the combination of both mutations is not additive, suggesting that these variants utilized alternate pathways to elicit similar alterations of the HIV-1 envelope structure.
authors.affiliation: Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Watkins
authors.forename: S
authors.initials: S
authors.lastname: Buge
authors.forename: K
authors.initials: K
authors.lastname: Aldrich
authors.forename: A E
authors.initials: AE
authors.lastname: Davis
authors.forename: J
authors.initials: J
authors.lastname: Robinson
authors.forename: M S
authors.initials: MS
authors.lastname: Reitz
authors.forename: M
authors.initials: M
authors.lastname: Robert-Guroff
mesh_terms: D000818:Animals; D001666:Binding Sites, Antibody; D015704:CD4 Antigens / Q000276:immunology; D019556:COS Cells; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D014644:Genetic Variation; D015483:HIV Antibodies / Q000276:immunology*; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D009500:Neutralization Tests; D017354:Point Mutation; D014407:Tumor Cells, Cultured
chemical_list: D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41