Immunogenicity of Stabilized HIV-1 Envelope Trimers with Reduced Exposure of Non-neutralizing Epitopes

被引：287

作者：

de Taeye, Steven W. ^{[1
]}

Ozorowski, Gabriel ^{[2
]}

de la Pena, Alba Torrents ^{[1
]}

Guttman, Miklos ^{[3
]}

Julien, Jean-Philippe ^{[2
]}

van den Kerkhof, Tom L. G. M. ^{[1
,4
]}

Burger, Judith A. ^{[1
]}

Pritchard, Laura K. ^{[5
]}

Pugach, Pavel ^{[6
]}

Yasmeen, Anila ^{[6
]}

Crampton, Jordan ^{[7
]}

Hu, Joyce ^{[7
]}

Bontjer, Ilja ^{[1
]}

Torres, Jonathan L. ^{[2
]}

Arendt, Heather ^{[8
]}

DeStefano, Joanne ^{[8
]}

Koff, Wayne C. ^{[8
]}

Schuitemaker, Hanneke ^{[4
]}

Eggink, Dirk ^{[1
]}

Berkhout, Ben ^{[1
]}

Dean, Hansi ^{[8
]}

LaBranche, Celia ^{[9
]}

Crotty, Shane ^{[7
]}

Crispin, Max ^{[5
]}

Montefiori, David C. ^{[9
]}

Klasse, P. J. ^{[6
]}

Lee, Kelly K. ^{[3
]}

Moore, John P. ^{[6
]}

Wilson, Ian A. ^{[2
,10
]}

Ward, Andrew B. ^{[2
]}

Sanders, Rogier W. ^{[1
,6
]}

机构：

[1] Univ Amsterdam, Acad Med Ctr, Dept Med Microbiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[2] Scripps Res Inst, IAVI Neutralizing Antibody Ctr & Collaborat AIDS, Scripps CHAVI ID, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[3] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA

[4] Univ Amsterdam, Acad Med Ctr, Dept Expt Immunol, NL-1105 AZ Amsterdam, Netherlands

[5] Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England

[6] Cornell Univ, Weill Med Coll, Dept Microbiol & Immunol, New York, NY 10021 USA

[7] Ctr HIV 1 AIDS Vaccine Immunol & Immunogen Discov, La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA

[8] Int AIDS Vaccine Initiat, New York, NY 10004 USA

[9] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA

[10] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

来源：

CELL | 2015年 / 163卷 / 07期

基金：

欧洲研究理事会; 美国国家卫生研究院;

关键词：

NEUTRALIZING ANTIBODY-RESPONSE; GLYCOPROTEIN COMPLEX; AFFINITY MATURATION; CRYSTAL-STRUCTURE; ENV TRIMERS; GP41; GP120; QUATERNARY; DESIGN; REGION;

D O I：

10.1016/j.cell.2015.11.056

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 and transient exposure of non-neutralizing, immunodominant epitopes 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, witha reducedability toundergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1BorTier-2NAb 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.

引用

页码：1702 / 1715

页数：14

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