A Human Monoclonal Antibody Neutralizes Diverse HIV-1 Isolates by Binding a Critical gp41 Epitope

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 con...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 41; pp. 14759 - 14764
Main Authors:	Miller, Michael D., Geleziunas, Romas, Bianchi, Elisabetta, Simon Lennard, Hrin, Renee, Hangchun Zhang, Lu, Meiqing, An, Zhiqiang, Ingallinella, Paolo, Finotto, Marco, Marco Mattu, Adam C. Finnefrock, Bramhill, David, Cook, James, Eckert, Debra M., Hampton, Richard, Patel, Mayuri, Stephen Jarantow, Joseph Joyce, Ciliberto, Gennaro, Cortese, Riccardo, Lu, Ping, William Strohl, Schleif, William, Michael Mc Elhaugh, Lane, Steven, Lloyd, Christopher, Lowe, David, Jane Osbourn, Tristan Vaughan, Emini, Emilio, Gaetano Barbato, Kim, Peter S., Hazuda, Daria J., Shiver, John W., Pessi, Antonello
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 11-10-2005 National Acad Sciences
Subjects:	Amino acids Antibodies Antibodies, Monoclonal - immunology Antigens Antivirals Binding sites Binding Sites, Antibody - genetics Binding Sites, Antibody - immunology Biological Sciences Epitopes Epitopes - genetics Epitopes - immunology HIV HIV 1 HIV Envelope Protein gp41 - genetics HIV Envelope Protein gp41 - immunology HIV-1 - immunology Human immunodeficiency virus Human immunodeficiency virus 1 Humans Inhibitory concentration 50 Luciferases Models, Molecular Neutralizing antibodies NMR Nuclear magnetic resonance Nuclear Magnetic Resonance, Biomolecular Polymerase Chain Reaction Protein Binding Viruses
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Summary:	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 fusioninhibitory 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 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. Present address: International AIDS Vaccine Initiative, New York, NY 10038. Contributed by Peter S. Kim, August 12, 2005 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. To whom correspondence may be addressed. E-mail: michael_miller1@merck.com or peter_kim@merck.com. Present address: University of Utah, Salt Lake City, UT 84132. Present address: Gilead Sciences, Inc., Foster City, CA 94404.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0506927102