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 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.
Miller
Michael D
MD
Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA. michael_miller1@merck.com
Geleziunas
Romas
R
Bianchi
Elisabetta
E
Lennard
Simon
S
Hrin
Renee
R
Zhang
Hangchun
H
Lu
Meiqing
M
An
Zhiqiang
Z
Ingallinella
Paolo
P
Finotto
Marco
M
Mattu
Marco
M
Finnefrock
Adam C
AC
Bramhill
David
D
Cook
James
J
Eckert
Debra M
DM
Hampton
Richard
R
Patel
Mayuri
M
Jarantow
Stephen
S
Joyce
Joseph
J
Ciliberto
Gennaro
G
Cortese
Riccardo
R
Lu
Ping
P
Strohl
William
W
Schleif
William
W
McElhaugh
Michael
M
Lane
Steven
S
Lloyd
Christopher
C
Lowe
David
D
Osbourn
Jane
J
Vaughan
Tristan
T
Emini
Emilio
E
Barbato
Gaetano
G
Kim
Peter S
PS
Hazuda
Daria J
DJ
Shiver
John W
JW
Pessi
Antonello
A
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
D000911:Antibodies, Monoclonal; D000939:Epitopes; D015700:HIV Envelope Protein gp41; D008156:Luciferases