A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope
- Michael D. Miller*,‡,†,
- Romas Geleziunas*,‡,§,
- Elisabetta Bianchi‡,¶,
- Simon Lennard‡,∥,
- Renee Hrin*,‡,
- Hangchun Zhang*,‡,
- Meiqing Lu*,‡,
- Zhiqiang An‡,**,
- Paolo Ingallinella‡,¶,
- Marco Finotto‡,¶,
- Marco Mattu‡,¶,
- Adam C. Finnefrock‡,**,
- David Bramhill‡,**,
- James Cook‡,**,
- Debra M. Eckert‡,**,††,
- Richard Hampton‡,**,
- Mayuri Patel‡,**,
- Stephen Jarantow‡,**,
- Joseph Joyce‡,**,
- Gennaro Ciliberto‡,¶,
- Riccardo Cortese‡,¶,
- Ping Lu‡,**,
- William Strohl‡,**,
- William Schleif‡,**,
- Michael McElhaugh‡,**,
- Steven Lane‡,∥,
- Christopher Lloyd‡,∥,
- David Lowe‡,∥,
- Jane Osbourn‡,∥,
- Tristan Vaughan‡,∥,
- Emilio Emini‡,**,‡‡,
- Gaetano Barbato‡,¶,
- Peter S. Kim‡,§§,†,
- Daria J. Hazuda*,‡,
- John W. Shiver‡,**, and
- Antonello Pessi‡,¶
- Departments of *Antiviral Research and **Vaccine and Biologics Research, and §§Office of the President, Merck Research Laboratories, West Point, PA 19486; ¶Istituto di Ricerche di Biologia Molecolare “P. Angeletti,” 00040 Pomezia, Rome, Italy; and ∥Cambridge Antibody Technology, Cambridge CB 16GH, United Kingdom
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Contributed by Peter S. Kim, August 12, 2005
Abstract
HIV-1 entry into cells is mediated by the envelope glycoprotein receptor-binding (gp120) and membrane fusion-promoting (gp41) subunits. The gp41 heptad repeat 1 (HR1) domain is the molecular target of the fusion-inhibitor drug enfuvirtide (T20). The HR1 sequence is highly conserved and therefore considered an attractive target for vaccine development, but it is unknown whether antibodies can access HR1. Herein, we use gp41-based peptides to select a human antibody, 5H/I1-BMV-D5 (D5), that binds to HR1 and inhibits the assembly of fusion intermediates in vitro. D5 inhibits the replication of diverse HIV-1 clinical isolates and therefore represents a previously unknown example of a crossneutralizing IgG selected by binding to designed antigens. NMR studies and functional analyses map the D5-binding site to a previously identified hydrophobic pocket situated in the HR1 groove. This hydrophobic pocket was proposed as a drug target and subsequently identified as a common binding site for peptide and peptidomimetic fusion inhibitors. The finding that the D5 fusion-inhibitory antibody shares the same binding site suggests that the hydrophobic pocket is a “hot spot” for fusion inhibition and an ideal target on which to focus a vaccine-elicited antibody response. Our data provide a structural framework for the design of new immunogens and therapeutic antibodies with crossneutralizing potential.
Footnotes
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↵ † To whom correspondence may be addressed. E-mail: michael_miller1{at}merck.com or peter_kim{at}merck.com.
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↵ ‡ All authors are current or former employees and stockholders of Merck & Co., Inc., or Cambridge Antibody Technology, and the research described herein was funded by these two companies.
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↵ § Present address: Gilead Sciences, Inc., Foster City, CA 94404.
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↵ †† Present address: University of Utah, Salt Lake City, UT 84132.
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↵ ‡‡ Present address: International AIDS Vaccine Initiative, New York, NY 10038.
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Abbreviations: HRn, heptad repeat n; 5H, five-helix; scFv, single-chain variable region fragment; HIVRP, HIV reporter particle; D5, 5H/I1-BMV-D5; T20, enfuvirtide.
- Copyright © 2005, The National Academy of Sciences
