Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer.

TitleComprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer.
Publication TypeJournal Article
Year of Publication2015
AuthorsDerking R, Ozorowski G, Sliepen K, Yasmeen A, Cupo A, Torres JL, Julien J-P, Lee J H, van Montfort T, de Taeye SW, Connors M, Burton DR, Wilson IA, Klasse P-J, Ward AB, Moore JP, Sanders RW
JournalPLoS Pathog
Volume11
Issue3
Paginatione1004767
Date Published03/25/2015
ISSN1553-7374
Abstract

The trimeric envelope (Env) spike is the focus of vaccine design efforts aimed at generating broadly neutralizing antibodies (bNAbs) to protect against HIV-1 infection. Three recent developments have facilitated a thorough investigation of the antigenic structure of the Env trimer: 1) the isolation of many bNAbs against multiple different epitopes; 2) the generation of a soluble trimer mimic, BG505 SOSIP.664 gp140, that expresses most bNAb epitopes; 3) facile binding assays involving the oriented immobilization of tagged trimers. Using these tools, we generated an antigenic map of the trimer by antibody cross-competition. Our analysis delineates three well-defined epitope clusters (CD4 binding site, quaternary V1V2 and Asn332-centered oligomannose patch) and new epitopes at the gp120-gp41 interface. It also identifies the relationships among these clusters. In addition to epitope overlap, we defined three more ways in which antibodies can cross-compete: steric competition from binding to proximal but non-overlapping epitopes (e.g., PGT151 inhibition of 8ANC195 binding); allosteric inhibition (e.g., PGT145 inhibition of 1NC9, 8ANC195, PGT151 and CD4 binding); and competition by reorientation of glycans (e.g., PGT135 inhibition of CD4bs bNAbs, and CD4bs bNAb inhibition of 8ANC195). We further demonstrate that bNAb binding can be complex, often affecting several other areas of the trimer surface beyond the epitope. This extensive analysis of the antigenic structure and the epitope interrelationships of the Env trimer should aid in design of both bNAb-based therapies and vaccines intended to induce bNAbs.

DOI10.1371/journal.ppat.1004767
Alternate JournalPLoS Pathog.
PubMed ID25807248
PubMed Central IDPMC4373910
Grant ListP01 AI082362 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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