Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes.
Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes.
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DOI：
10.1016/j.cell.2015.11.056
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发表时间：
2015-12-17
期刊：
影响因子：
64.5
通讯作者：
Sanders RW
中科院分区：
文献类型：
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作者：
de Taeye SW;Ozorowski G;Torrents de la Peña A;Guttman M;Julien JP;van den Kerkhof TL;Burger JA;Pritchard LK;Pugach P;Yasmeen A;Crampton J;Hu J;Bontjer I;Torres JL;Arendt H;DeStefano J;Koff WC;Schuitemaker H;Eggink D;Berkhout B;Dean H;LaBranche C;Crotty S;Crispin M;Montefiori DC;Klasse PJ;Lee KK;Moore JP;Wilson IA;Ward AB;Sanders RW
包膜糖蛋白三聚体介导HIV-1进入细胞。三聚体是灵活的，在封闭和更开放的构象之间波动，有时采样完全开放的CD 4结合形式。我们假设构象的灵活性可能会阻碍广泛中和抗体（bNAbs）的诱导。因此，我们修饰了可溶性Env三聚体以稳定它们的封闭基态。三聚体变体确实稳定在闭合构象中，具有降低的经历受体诱导的构象变化的能力和降低的非中和V3定向抗体表位的暴露。在兔中，稳定的三聚体诱导的自体Tier-1B或Tier-2 NAb滴度与相应野生型三聚体诱导的相似，但V3定向的Tier-1A NAb水平较低。因此，稳定的封闭三聚体可能是旨在诱导bNAb的疫苗的有用组分。
The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers, but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs.