title: Antibody neutralization escape mediated by point mutations in the intracytoplasmic tail of human immunodeficiency virus type 1 gp41.
abstract: The persistence of human immunodeficiency virus type 1 (HIV-1) infection in the presence of robust host immunity has been associated in part with variation in viral envelope proteins leading to antigenic variation and escape from neutralizing antibodies. Previous studies of natural neutralization escape mutants have predominantly focused on gp120 and gp41 ectodomain sequence variations that alter antibody binding via changes in conformation or glycosylation pattern of the Env, likely due to the immune pressure exerted on the exposed ectodomain component of the glycoprotein. Here, we show for the first time a novel mechanism by which point mutations in the intracytoplasmic tail of the transmembrane component (gp41) of envelope can render the virus resistant to neutralization by monoclonal antibodies and broadly neutralizing polyclonal serum antibodies. Point mutations in a highly conserved structural motif within the intracytoplasmic tail resulted in decreased binding of neutralizing antibodies to the Env ectodomain, evidently due to allosteric changes both in the gp41 ectodomain and in gp120. While receptor binding and infectivity of the mutant virus remained unaltered, the changes in Env antigenicity were associated with an increase in neutralization resistance of the mutant virus. These studies demonstrate the structurally integrated nature of gp120 and gp41 and underscore a previously unrecognized potentially critical role for even minor sequence variation of the intracytoplasmic tail in modulating the antigenicity of the ectodomain of HIV-1 envelope glycoprotein complex.
authors.affiliation: University of Pittsburgh, Department of Molecular Genetics and Biochemistry, School of Medicine, W1144 BST, Pittsburgh, PA 15261, USA.
authors.forename: Vandana
authors.initials: V
authors.lastname: Kalia
authors.forename: Surojit
authors.initials: S
authors.lastname: Sarkar
authors.forename: Phalguni
authors.initials: P
authors.lastname: Gupta
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Montelaro
mesh_terms: D000918:Antibody Specificity; D002460:Cell Line; D014644:Genetic Variation; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D009154:Mutation; D009500:Neutralization Tests; D017354:Point Mutation
chemical_list: D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41