title: Rapid progression to simian AIDS can be accompanied by selection of CD4-independent gp120 variants with impaired ability to bind CD4.
abstract: Aspartate 368 on human immunodeficiency virus type 1 (HIV-1) gp120 forms multiple contacts with CD4; in mutagenesis studies, its replacement by asparagine and corresponding changes in simian immunodeficiency virus SIVmac (D385N) reduced binding with CD4. Nevertheless, simian immunodeficiency virus envelopes with D385N were prevalent in several studies. Extending these observations, we also found D385N to be dominant among env clones from two rhesus macaques that progressed rapidly to simian AIDS. These envelopes showed a CD4-independent phenotype as well as reduced affinity to CD4. Moreover, an adjacent change, G383R, which was frequently coselected with D385N, further decreased binding. An optical biosensor study demonstrated that the SIVmac239 gp120 bound to CD4 with kinetics similar to those of HIV-1. However, the gp120s with D385N and G383R showed a 40-fold reduction in affinity, with a drastic increase in dissociation rate, indicating an inherently unstable complex. This finding showed that rapid progression to simian AIDS may be accompanied by the selection of CD4-independent gp120 variants with impaired CD4 binding ability.
authors.affiliation: Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ryzhova
authors.forename: J Charles
authors.initials: JC
authors.lastname: Whitbeck
authors.forename: Gabriela
authors.initials: G
authors.lastname: Canziani
authors.forename: Susan V
authors.initials: SV
authors.lastname: Westmoreland
authors.forename: Gary H
authors.initials: GH
authors.lastname: Cohen
authors.forename: Roselyn J
authors.initials: RJ
authors.lastname: Eisenberg
authors.forename: Andrew
authors.initials: A
authors.lastname: Lackner
authors.forename: Francisco
authors.initials: F
authors.lastname: González-Scarano
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D018450:Disease Progression; D014644:Genetic Variation; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000401:mortality / Q000503:physiopathology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D020349:Surface Plasmon Resonance; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus