Abstract

HIV-1 envelope (Env) mimetics are candidate components of prophylactic vaccines and potential therapeutics. Here we use a synthetic V3-glycopeptide (“Man9-V3”) for structural studies of an HIV Env third variable loop (V3)-glycan directed, broadly neutralizing antibody (bnAb) lineage (“DH270”), to visualize the epitope on Env and to study how affinity maturation of the lineage proceeded. Unlike many previous V3 mimetics, Man9-V3 encompasses two key features of the V3 region recognized by V3-glycan bnAbs—the conserved GDIR motif and the N332 glycan. In our structure of an antibody fragment of a lineage member, DH270.6, in complex with the V3 glycopeptide, the conformation of the antibody-bound glycopeptide conforms closely to that of the corresponding segment in an intact HIV-1 Env trimer. An additional structure identifies roles for two critical mutations in the development of breadth. The results suggest a strategy for use of a V3 glycopeptide as a vaccine immunogen.

Details

Title
HIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope
Author
Fera, Daniela 1   VIAFID ORCID Logo  ; Lee, Matthew S 1 ; Wiehe, Kevin 2 ; R Ryan Meyerhoff 3 ; Piai, Alessandro 4   VIAFID ORCID Logo  ; Bonsignori, Mattia 2 ; Aussedat, Baptiste 5 ; Walkowicz, William E 5 ; Ton, Therese 6 ; Zhou, Jeffrey O 7 ; Danishefsky, Samuel 5 ; Haynes, Barton F 2 ; Harrison, Stephen C 8 

1  Laboratory of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA 
2  Department of Medicine, Duke University School of Medicine, Duke University Medical Center, Durham, NC, USA; Duke Human Vaccine Institute, Durham, NC, USA 
3  Duke Human Vaccine Institute, Durham, NC, USA; Department of Immunology, Duke University School of Medicine, Duke University Medical Center, Durham, NC, USA 
4  Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA 
5  Department of Bioorganic Chemistry, Sloan Kettering Institute, New York, NY, USA 
6  Department of Biology, Swarthmore College, Swarthmore, PA, USA 
7  Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA, USA 
8  Laboratory of Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA 
Pages
1-11
Publication year
2018
Publication date
Mar 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-03565-6
ProQuest document ID
2014497065
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.