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Journal of Virology, April 2004, p. 3742-3752, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3742-3752.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155

Navid Madani,1,2 Ana Luisa Perdigoto,1 Kumar Srinivasan,1,2 Jason M. Cox,3 Jason J. Chruma,3 Judith LaLonde,4 Martha Head,4 Amos B. Smith III,3 and Joseph G. Sodroski1,2,5*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,1 Department of Pathology and Division of AIDS, Harvard Medical School,2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115,5 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104,3 GlaxoSmithKline, King of Prussia, Pennsylvania 194064

Received 18 September 2003/ Accepted 4 December 2003

BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the "phenylalanine 43 cavity" and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.

* Corresponding author. Mailing address: Jimmy Fund Building, Rm. 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.

Journal of Virology, April 2004, p. 3742-3752, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3742-3752.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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