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Journal of Virology, February 2003, p. 1666-1671, Vol. 77, No. 3
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.3.1666-1671.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Peptides Trap the Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Fusion Intermediate at Two Sites

Center for Biologics Evaluation and Research, Food and Drug Administration,¹ National Institute for Arthritis and Musculoskeletal Diseases, National Institutes of Health, Bethesda, Maryland 20892²

Received 4 June 2002/ Accepted 22 October 2002

Human immunodeficiency virus type 1 (HIV-1) entry into target cells requires folding of two heptad-repeat regions (N-HR and C-HR) of gp41 into a trimer of N-HR and C-HR hairpins, which brings viral and target cell membranes together to facilitate membrane fusion. Peptides corresponding to the N-HR and C-HR of gp41 are potent inhibitors of HIV infection. Here we report new findings on the mechanism of inhibition of a N-HR peptide and compare these data with inhibition by a C-HR peptide. Using intact envelope glycoprotein (Env) under fusogenic conditions, we show that the N-HR peptide preferentially binds receptor-activated Env and that CD4 binding is sufficient for triggering conformational changes that allow the peptide to bind Env, results similar to those seen with the C-HR peptide. However, activation by both CD4 and chemokine receptors further enhances Env binding by both peptides. We also show that a nonconservative mutation in the N-HR of gp41 abolishes C-HR peptide but not N-HR peptide binding to gp41. These results indicate that there are two distinct sites in receptor-activated Env that are potential targets for drug or vaccine development.

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