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J. Biol. Chem., Vol. 280, Issue 13, 12567-12572, April 1, 2005

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Steric Accessibility of the HIV-1 gp41 N-trimer Region^*

Agnes E. Hamburger¶, Sunghwan Kim||, Brett D. Welch||, and Michael S. Kay||**

From the ^||Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, Utah, 84132 and the Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

During human immunodeficiency virus entry, gp41 undergoes a series of conformational changes that induce membrane fusion. Immediately prior to fusion, gp41 exists in a prehairpin intermediate in which the N- and C-peptide regions of gp41 are exposed. Rearrangement of this intermediate into a six-helix bundle composed of a trimeric coiled coil from the N-peptide region (N-trimer) surrounded by three peptides from the C-peptide region provides the driving force for membrane fusion, whereas prevention of six-helix bundle formation inhibits viral entry. Because of its central role in mediating viral entry, the N-trimer region of gp41 is a key vaccine target. Extensive efforts to discover potent and broadly neutralizing antibodies (Abs) against the N-trimer region have, thus far, been unsuccessful. In this study, we attached a potent C-peptide inhibitor that binds to the N-trimer region to cargo proteins of various sizes to examine the steric accessibility of the N-trimer during fusion. These inhibitors show a progressive loss of potency with increasing cargo size. Extension of the cargo/C-peptide linker partially restores inhibitory potency. These results demonstrate that the human immunodeficiency virus defends its critical hairpin-forming machinery by steric exclusion of large proteins and may explain the current dearth of neutralizing Abs against the N-trimer. In contrast, previous results suggest the C-peptide region is freely accessible during fusion, demonstrating that the N- and C-peptide regions are in structurally distinct environments. Based on these results, we also propose new strategies for the generation of neutralizing Abs that overcome this steric block.

Received for publication, November 11, 2004 , and in revised form, January 4, 2005.

^* This work was supported in part by National Institutes of Health Grant P01GM066521 (to M. S. K.) and a National Institutes of Health training grant in biological chemistry (to B. D. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Present address: Dept. of Biology, 114-96, California Institute of Technology, Pasadena, CA 91125.

^** To whom correspondence should be addressed: Dept. of Biochemistry, MREB 211, 50 N. Medical Dr., Salt Lake City, UT 84132. Tel.: 801-585-5021; Fax: 801-581-7959; E-mail: kay{at}biochem.utah.edu.

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