title: Neutralization sensitivity of HIV-1 Env-pseudotyped virus clones is determined by co-operativity between mutations which modulate the CD4-binding site and those that affect gp120-gp41 stability.
abstract: Adaptation of antibody neutralization-resistant human immunodeficiency virus type I (HIV-1) to growth in vitro generally results in the acquisition of a neutralization-sensitive phenotype, an alteration of viral growth kinetics, and an array of amino acid substitutions associated with these changes. Here we examine a panel of Env chimeras and mutants derived from these neutralization-resistant and -sensitive parental Envs. A range of neutralization and infectivity phenotypes was observed. These included a modulation of the CD4 binding site (CD4bs) towards recognition by neutralizing and non-neutralizing CD4bs-directed antibodies, resulting in a globally neutralization-sensitive Env; alterations which affected Env complex stability; and interactions which resulted in differential infectivity and CCR5/CXCR4 usage. This range of properties resulted from the complex interactions of no more than three amino acids found in key Env locations. These data add to a growing body of evidence that dramatic functional alterations of the native oligomeric Env protein complex can result from relatively minor amino acid substitutions.
authors.affiliation: Jefferiss Research Trust Laboratories, Wright Fleming Institute, Imperial College School of Medicine, London, UK. sib2005@med.cornell.edu
authors.forename: Simon
authors.initials: S
authors.lastname: Beddows
authors.forename: Natalie N
authors.initials: NN
authors.lastname: Zheng
authors.forename: Carolina
authors.initials: C
authors.lastname: Herrera
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Michael
authors.forename: Kelly
authors.initials: K
authors.lastname: Barnes
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Rod S
authors.initials: RS
authors.lastname: Daniels
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Weber
mesh_terms: D001665:Binding Sites; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests
chemical_list: D015704:CD4 Antigens; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41