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Journal of Virology, August 2002, p. 7903-7909, Vol. 76, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.15.7903-7909.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Rapid Progression to Simian AIDS Can Be Accompanied by Selection of CD4-Independent gp120 Variants with Impaired Ability To Bind CD4

Elena Ryzhova,1 J. Charles Whitbeck,2 Gabriela Canziani,3,{dagger} Susan V. Westmoreland,4 Gary H. Cohen,2 Roselyn J. Eisenberg,5 Andrew Lackner,4,{ddagger} and Francisco González-Scarano1,6*

Departments of Neurology (School of Medicine),,1 Microbiology (School of Dental Medicine),,2 Medicine (School of Medicine),,3 Pathobiology (School of Veterinary Medicine),5 Microbiology (School of Medicine), University of Pennsylvania, Philadelphia, Pennsylvania 19104,6 New England Primate Research Center, Harvard School of Medicine, Southborough, Massachusetts 017724

Received 24 January 2002/ Accepted 4 May 2002

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.

* Corresponding author. Mailing address: Department of Neurology, University of Pennsylvania Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104-0146. Phone: (215) 662-3360. Fax: (215) 662-3362. E-mail: scarano{at}mail.med.upenn.edu.

{dagger} Present address: School of Medicine, University of Utah, Salt Lake City, UT 84132.

{ddagger} Present address: Tulane Regional Primate Research Center, Covington, LA 70433.

Journal of Virology, August 2002, p. 7903-7909, Vol. 76, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.15.7903-7909.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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