title: CD4-binding site alterations in CCR5-using HIV-1 envelopes influencing gp120-CD4 interactions and fusogenicity.
abstract: CD4-binding site (CD4bs) alterations in gp120 contribute to different pathophysiological phenotypes of CCR5-using (R5) HIV-1 strains, but the potential structural basis is unknown. Here, we characterized functionally diverse R5 envelope (Env) clones (n=16) to elucidate potential structural alterations within the gp120 CD4bs that influence Env function. Initially, we showed that the magnitude of gp120-CD4-binding correlates with increased fusogenicity and reduced CD4 dependence. Analysis of three-dimensional gp120 structural models revealed two CD4bs variants, D279 and N362, that were associated with reduced CD4 dependence. Further structural analysis showed that a wider aperture of the predicted CD4bs cavity, as constrained by the inner-most atoms at the gp120 V1V2 stem and the V5 loop, was associated with amino acid alterations within V5 and correlated with increased gp120-CD4 binding and increased fusogenicity. Our results provide evidence that the gp120 V5 loop may alter CD4bs conformation and contribute to increased gp120-CD4 interactions and Env fusogenicity.
authors.affiliation: Center for Virology, Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Jasminka
authors.initials: J
authors.lastname: Sterjovski
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Churchill
authors.forename: Michael
authors.initials: M
authors.lastname: Roche
authors.forename: Anne
authors.initials: A
authors.lastname: Ellett
authors.forename: William
authors.initials: W
authors.lastname: Farrugia
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wesselingh
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Cunningham
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism*; D004252:DNA Mutational Analysis; D015699:HIV Envelope Protein gp120 / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D050505:Mutant Proteins; D019713:Receptors, CCR5; C514793:gp120 protein, Human immunodeficiency virus 1