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 CilibertoRiccardo 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, Antonello Pessi

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14759-14764
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number41
DOIs
Publication statusPublished - Oct 11 2005

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HIV-1
Epitopes
Monoclonal Antibodies
Antibodies
Binding Sites
Vaccines
Peptidomimetics
Peptides
Membrane Fusion
Pharmaceutical Preparations
Antibody Formation
Glycoproteins
Immunoglobulin G
Antigens
Therapeutics

Keywords

  • Envelope
  • Fusion
  • Prehairpin
  • Vaccine

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope. / Miller, Michael D.; Geleziunas, Romas; Bianchi, Elisabetta; Lennard, Simon; Hrin, Renee; Zhang, Hangchun; Lu, Meiqing; An, Zhiqiang; Ingallinella, Paolo; Finotto, Marco; Mattu, Marco; Finnefrock, Adam C.; Bramhill, David; Cook, James; Eckert, Debra M.; Hampton, Richard; Patel, Mayuri; Jarantow, Stephen; Joyce, Joseph; Ciliberto, Gennaro; Cortese, Riccardo; Lu, Ping; Strohl, William; Schleif, William; McElhaugh, Michael; Lane, Steven; Lloyd, Christopher; Lowe, David; Osbourn, Jane; Vaughan, Tristan; Emini, Emilio; Barbato, Gaetano; Kim, Peter S.; Hazuda, Daria J.; Shiver, John W.; Pessi, Antonello.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 41, 11.10.2005, p. 14759-14764.

Research output: Contribution to journalArticle

Miller, MD, Geleziunas, R, Bianchi, E, Lennard, S, Hrin, R, Zhang, H, Lu, M, An, Z, Ingallinella, P, Finotto, M, Mattu, M, Finnefrock, AC, Bramhill, D, Cook, J, Eckert, DM, Hampton, R, Patel, M, Jarantow, S, Joyce, J, Ciliberto, G, Cortese, R, Lu, P, Strohl, W, Schleif, W, McElhaugh, M, Lane, S, Lloyd, C, Lowe, D, Osbourn, J, Vaughan, T, Emini, E, Barbato, G, Kim, PS, Hazuda, DJ, Shiver, JW & Pessi, A 2005, 'A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 41, pp. 14759-14764. https://doi.org/10.1073/pnas.0506927102
Miller, Michael D. ; Geleziunas, Romas ; Bianchi, Elisabetta ; Lennard, Simon ; Hrin, Renee ; Zhang, Hangchun ; Lu, Meiqing ; An, Zhiqiang ; Ingallinella, Paolo ; Finotto, Marco ; Mattu, Marco ; Finnefrock, Adam C. ; Bramhill, David ; Cook, James ; Eckert, Debra M. ; Hampton, Richard ; Patel, Mayuri ; Jarantow, Stephen ; Joyce, Joseph ; Ciliberto, Gennaro ; Cortese, Riccardo ; Lu, Ping ; Strohl, William ; Schleif, William ; McElhaugh, Michael ; Lane, Steven ; Lloyd, Christopher ; Lowe, David ; Osbourn, Jane ; Vaughan, Tristan ; Emini, Emilio ; Barbato, Gaetano ; Kim, Peter S. ; Hazuda, Daria J. ; Shiver, John W. ; Pessi, Antonello. / A human monoclonal antibody neutralizes diverse HIV-1 isolates by binding a critical gp41 epitope. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 41. pp. 14759-14764.
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AU - Bianchi, Elisabetta

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AU - Hrin, Renee

AU - Zhang, Hangchun

AU - Lu, Meiqing

AU - An, Zhiqiang

AU - Ingallinella, Paolo

AU - Finotto, Marco

AU - Mattu, Marco

AU - Finnefrock, Adam C.

AU - Bramhill, David

AU - Cook, James

AU - Eckert, Debra M.

AU - Hampton, Richard

AU - Patel, Mayuri

AU - Jarantow, Stephen

AU - Joyce, Joseph

AU - Ciliberto, Gennaro

AU - Cortese, Riccardo

AU - Lu, Ping

AU - Strohl, William

AU - Schleif, William

AU - McElhaugh, Michael

AU - Lane, Steven

AU - Lloyd, Christopher

AU - Lowe, David

AU - Osbourn, Jane

AU - Vaughan, Tristan

AU - Emini, Emilio

AU - Barbato, Gaetano

AU - Kim, Peter S.

AU - Hazuda, Daria J.

AU - Shiver, John W.

AU - Pessi, Antonello

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KW - Envelope

KW - Fusion

KW - Prehairpin

KW - Vaccine

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