A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies

doi:10.1073/pnas.0800255105

A fusion-intermediate state of HIV-1 gp41 targeted by broadly neutralizing antibodies

*Laboratory of Molecular Medicine, Children's Hospital, and Department of Pediatrics, Harvard Medical School, 320 Longwood Avenue, Boston, MA 02115;
^†Jack and Eileen Connors Structural Biology Laboratory, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115;
^‡Howard Hughes Medical Institute, 320 Longwood Avenue, Boston, MA 02115;
^§Program in Virology, Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115; and
^¶Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158

Communicated by Stephen C. Harrison, Children's Hospital Boston, Boston, MA, January 10, 2008 (received for review December 18, 2007)

Abstract

Most antibodies induced by HIV-1 are ineffective at preventing initiation or spread of infection because they are either nonneutralizing or narrowly isolate-specific. Rare, “broadly neutralizing” antibodies have been detected that recognize relatively conserved regions on the envelope glycoprotein. Using stringently characterized, homogeneous preparations of trimeric HIV-1 envelope protein in relevant conformations, we have analyzed the molecular mechanism of neutralization by two of these antibodies, 2F5 and 4E10. We find that their epitopes, in the membrane-proximal segment of the envelope protein ectodomain, are exposed only on a form designed to mimic an intermediate state during viral entry. These results help explain the rarity of 2F5- and 4E10-like antibody responses and suggest a strategy for eliciting them.

Footnotes

^‖To whom correspondence should be addressed. E-mail: bchen{at}crystal.harvard.edu
Author contributions: G.F. and B.C. designed research; G.F., H.P., S.R.-V., M.M., Y.C., and B.C. performed research; M.M. and Y.C. contributed new reagents/analytic tools; G.F. and B.C. analyzed data; and B.C. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0800255105/DC1.