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

Lee, Jeong Hyun; Andrabi, Raiees; Su, Ching-Yao; Yasmeen, Anila; Julien, Jean-Philippe; Kong, Leopold; Wu, Nicholas C.; McBride, Ryan; Sok, Devin; Pauthner, Matthias; Cottrell, Christopher A.; Nieusma, Travis; Blattner, Claudia; Paulson, James C.; Klasse, Per Johan; Wilson, Ian A.; Burton, Dennis R.; Ward, Andrew B.

doi:10.1016/j.immuni.2017.03.017

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

Journal Article · Sat Apr 01 00:00:00 EDT 2017 · Immunity

DOI:https://doi.org/10.1016/j.immuni.2017.03.017· OSTI ID:1399607

Lee, Jeong Hyun; Andrabi, Raiees; Su, Ching-Yao; Yasmeen, Anila; Julien, Jean-Philippe; Kong, Leopold; Wu, Nicholas C.; McBride, Ryan; Sok, Devin; Pauthner, Matthias; Cottrell, Christopher A.; Nieusma, Travis; Blattner, Claudia; Paulson, James C.; Klasse, Per Johan; Wilson, Ian A.; Burton, Dennis R.; Ward, Andrew B.

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Cancer Inst.; National Inst. of General Medical Sciences

Grant/Contract Number:: AC02-06CH11357; ACB-12002; AGM-12006

OSTI ID:: 1399607

Alternate ID(s):: OSTI ID: 1368261

Journal Information:: Immunity, Journal Name: Immunity Vol. 46 Journal Issue: 4; ISSN 1074-7613

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 160 works

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59 BASIC BIOLOGICAL SCIENCES
HIV
envelope glycoprotein
PGT145
broadly neutralizing antibody
trimer apex
cryo-electron microscopy

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

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