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Antigenicity and Immunogenicity of HIV-1 Envelope Trimers complexed to a Small-Molecule Viral Entry Inhibitor.
- Source :
-
Journal of Virology . 2020, Vol. 94 Issue 21, p1-51. 51p. - Publication Year :
- 2020
-
Abstract
- Small-molecule viral entry inhibitors, like BMS-626529 (BMS-529), allosterically block CD4 binding to HIV-1 Envelope (Env) and inhibit CD4-induced structural changes in Env trimers. Here we show that the binding of BMS-529 to clade C soluble chimeric gp140 SOSIP (ch.SOSIP) and membrane-bound trimers with intact transmembrane domain (gp150) prevented trimer conformational transitions and enhanced their immunogenicity. When complexed to BMS-529, ch.SOSIP trimers retained their binding to bnAbs and to their unmutated common ancestor (UCA) antibodies, while exposure of CD4-induced (CD4i) non-bnAb epitopes was inhibited. BMS-529 complexed gp150 trimers in detergent micelles, which were isolated from CHO cells, bound to bnAbs, including UCA and intermediates of the CD4 binding-site (bs) CH103 bnAb lineage, showed limited exposure of CD4i epitopes and a glycosylation pattern with a preponderance of high-mannose glycans. In rabbits, BMS-529-complexed V3 glycan-targeting ch.SOSIP immunogen induced in the majority of immunized animals higher neutralization titers against both autologous and select high mannose-bearing heterologous tier 2 pseudoviruses than those immunized with the non-complexed ch.SOSIP. In rhesus macaques, BMS-529 complexed to CD4 bs-targeting ch.SOSIP immunogen induced stronger neutralization against tier 2 pseudoviruses bearing high mannose glycans, when compared to non-complexed ch.SOSIP trimer immunogen. When immunized with gp150 complexed to BMS-529, rhesus macaques showed neutralization against tier 2 pseudoviruses with targeted glycan deletion and high mannose glycan enrichment. These results demonstrated that stabilization of Env trimer conformation with BMS-529 improved the immunogenicity of select chimeric SOSIP trimers and elicited tier 2 neutralizing antibodies of higher potency than non-complexed trimers. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 0022538X
- Volume :
- 94
- Issue :
- 21
- Database :
- Academic Search Index
- Journal :
- Journal of Virology
- Publication Type :
- Academic Journal
- Accession number :
- 146502000
- Full Text :
- https://doi.org/10.1128/JVI.00958-20