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

Virology. 2005 Jun 20;337(1):136-48. doi: 10.1016/j.virol.2005.03.033.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • CD4 Antigens / genetics
  • CD4 Antigens / metabolism*
  • HIV Antibodies / immunology*
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / immunology
  • HIV Envelope Protein gp41 / metabolism*
  • HIV-1 / metabolism
  • HIV-1 / physiology*
  • Humans
  • Molecular Sequence Data
  • Neutralization Tests

Substances

  • CD4 Antigens
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41

Associated data

  • GENBANK/AY973156