Structural basis for HIV-1 neutralization by a gp41 fusion intermediate-directed antibody.
Elicitation of potent and broadly neutralizing antibodies is an important goal in designing an effective human immunodeficiency virus-1 (HIV-1) vaccine. The HIV-1 gp41 inner-core trimer represents a functionally and structurally conserved target for therapeutics. Here we report the 2.0-A-resolution crystal structure of the complex between the antigen-binding fragment of D5, an HIV-1 cross-neutralizing antibody, and 5-helix, a gp41 inner-core mimetic. Both binding and neutralization depend on residues in the D5 CDR H2 loop protruding into the conserved gp41 hydrophobic pocket, as well as a large pocket in D5 surrounding core gp41 residues. Kinetic analysis of D5 mutants with perturbed D5-gp41 interactions suggests that D5 persistence at the fusion intermediate is crucial for neutralization. Thus, our data validate the gp41 N-peptide trimer fusion intermediate as a target for neutralizing antibodies and provide a template for identification of more potent and broadly neutralizing molecules.
Luftig
Micah A
MA
Istituto di Ricerche di Biologia Molecolare P. Angeletti, Via Pontina Km 30,600, I-00040 Pomezia (Rome), Italy.
Mattu
Marco
M
Di Giovine
Paolo
P
Geleziunas
Romas
R
Hrin
Renee
R
Barbato
Gaetano
G
Bianchi
Elisabetta
E
Miller
Michael D
MD
Pessi
Antonello
A
Carfí
Andrea
A
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007930:Leucine / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D009500:Neutralization Tests; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014364:Tryptophan / Q000737:chemistry
D000911:Antibodies, Monoclonal; D015700:HIV Envelope Protein gp41; D011993:Recombinant Fusion Proteins; D014364:Tryptophan; D007930:Leucine