title: A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope.
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.
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA. michael_miller1@merck.com
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Elisabetta
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authors.lastname: Bianchi
authors.forename: Simon
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authors.lastname: Lennard
authors.forename: Renee
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authors.lastname: Hrin
authors.forename: Hangchun
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authors.lastname: Zhang
authors.forename: Meiqing
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authors.lastname: Lu
authors.forename: Zhiqiang
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authors.lastname: An
authors.forename: Paolo
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authors.lastname: Ingallinella
authors.forename: Marco
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authors.lastname: Finotto
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authors.lastname: Mattu
authors.forename: Adam C
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authors.lastname: Finnefrock
authors.forename: David
authors.initials: D
authors.lastname: Bramhill
authors.forename: James
authors.initials: J
authors.lastname: Cook
authors.forename: Debra M
authors.initials: DM
authors.lastname: Eckert
authors.forename: Richard
authors.initials: R
authors.lastname: Hampton
authors.forename: Mayuri
authors.initials: M
authors.lastname: Patel
authors.forename: Stephen
authors.initials: S
authors.lastname: Jarantow
authors.forename: Joseph
authors.initials: J
authors.lastname: Joyce
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.forename: Riccardo
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authors.lastname: Cortese
authors.forename: Ping
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authors.lastname: Lu
authors.forename: William
authors.initials: W
authors.lastname: Strohl
authors.forename: William
authors.initials: W
authors.lastname: Schleif
authors.forename: Michael
authors.initials: M
authors.lastname: McElhaugh
authors.forename: Steven
authors.initials: S
authors.lastname: Lane
authors.forename: Christopher
authors.initials: C
authors.lastname: Lloyd
authors.forename: David
authors.initials: D
authors.lastname: Lowe
authors.forename: Jane
authors.initials: J
authors.lastname: Osbourn
authors.forename: Tristan
authors.initials: T
authors.lastname: Vaughan
authors.forename: Emilio
authors.initials: E
authors.lastname: Emini
authors.forename: Gaetano
authors.initials: G
authors.lastname: Barbato
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kim
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: John W
authors.initials: JW
authors.lastname: Shiver
authors.forename: Antonello
authors.initials: A
authors.lastname: Pessi
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008156:Luciferases; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D016133:Polymerase Chain Reaction; D011485:Protein Binding
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D015700:HIV Envelope Protein gp41; D008156:Luciferases