A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure.

TitleA Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic β-Hairpin Structure.
Publication TypeJournal Article
Year of Publication2017
AuthorsLee J H, Andrabi R, Su C-Y, Yasmeen A, Julien J-P, Kong L, Wu NC, McBride R, Sok D, Pauthner M, Cottrell CA, Nieusma T, Blattner C, Paulson JC, Klasse P J, Wilson IA, Burton DR, Ward AB
JournalImmunity
Volume46
Issue4
Pagination690-702
Date Published04/18/2017
ISSN1097-4180
Abstract

Broadly neutralizing antibodies (bnAbs) to HIV delineate vaccine targets and are prophylactic and therapeutic agents. Some of the most potent bnAbs target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer. Using cryo-electron microscopy, we solved the atomic structure of an apex bnAb, PGT145, in complex with Env. We showed that the long anionic HCDR3 of PGT145 penetrated between glycans at the trimer 3-fold axis, to contact peptide residues from all three Env protomers, and thus explains its highly trimer-specific nature. Somatic hypermutation in the other CDRs of PGT145 were crucially involved in stabilizing the structure of the HCDR3, similar to bovine antibodies, to aid in recognition of a cluster of conserved basic residues hypothesized to facilitate trimer disassembly during viral entry. Overall, the findings exemplify the creative solutions that the human immune system can evolve to recognize a conserved motif buried under a canopy of glycans.

DOI10.1016/j.immuni.2017.03.017
Alternate JournalImmunity
PubMed ID28423342
PubMed Central IDPMC5400778
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