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Journal of Virology, October 2002, p. 9888-9899, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9888-9899.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Mutagenic Stabilization and/or Disruption of a CD4-Bound State Reveals Distinct Conformations of the Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein

Shi-Hua Xiang,1 Peter D. Kwong,2,3 Rishi Gupta,1 Carlo D. Rizzuto,1 David J. Casper,4 Richard Wyatt,1,2 Liping Wang,1 Wayne A. Hendrickson,3 Michael L. Doyle,4,{dagger} and Joseph Sodroski1,5*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Pathology, Division of AIDS, Harvard Medical School,1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115,5 Vaccine Research Center, National Institutes of Health, Bethesda, Maryland 20892,2 Department of Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute, Columbia University, New York, New York 10032,3 Department of Structural Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 194064

Received 1 April 2002/ Accepted 30 June 2002

The human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein is conformationally flexible. Upon binding to the host cell receptor CD4, gp120 assumes a conformation that is recognized by the second receptor, CCR5 and/or CXCR4, and by the CD4-induced (CD4i) antibodies. Guided by the X-ray crystal structure of a gp120-CD4-CD4i antibody complex, we introduced changes into gp120 that were designed to stabilize or disrupt this conformation. One mutant, 375 S/W, in which the tryptophan indole group is predicted to occupy the Phe 43 cavity in the gp120 interior, apparently favors a gp120 conformation closer to that of the CD4-bound state. The 375 S/W mutant was recognized as well as or better than wild-type gp120 by CD4 and CD4i antibodies, and the large decrease in entropy observed when wild-type gp120 bound CD4 was reduced for the 375 S/W mutant. The recognition of the 375 S/W mutant by CD4BS antibodies, which are directed against the CD4-binding region of gp120, was markedly reduced compared with that of the wild-type gp120. Compared with the wild-type virus, viruses with the 375 S/W envelope glycoproteins were resistant to neutralization by IgG1b12, a CD4BS antibody, were slightly more sensitive to soluble CD4 neutralization and were neutralized more efficiently by the 2G12 antibody. Another mutant, 423 I/P, in which the gp120 bridging sheet was disrupted, did not bind CD4, CCR5, or CD4i antibodies, even though recognition by CD4BS antibodies was efficient. These results indicate that CD4BS antibodies recognize conformations of gp120 different from that recognized by CD4 and CD4i antibodies.

* Corresponding author. Mailing address: Jimmy Fund Building, Room 824, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Phone: (617) 632-3371. Fax: (617) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.

{dagger} Present address: Biopharmaceuticals Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000.

Journal of Virology, October 2002, p. 9888-9899, Vol. 76, No. 19
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.19.9888-9899.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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