Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization

被引：123

作者：

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

Julien, Jean-Philippe ^{[2
,3
,11
,12
,13
]}

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

Garces, Fernando ^{[2
,3
,14
]}

Guttman, Miklos ^{[4
]}

Ozorowski, Gabriel ^{[2
,3
]}

Pritchard, Laura K. ^{[5
]}

Behrens, Anna-Janina ^{[5
]}

Go, Eden P. ^{[6
]}

Burger, Judith A. ^{[1
]}

Schermer, Edith E. ^{[1
]}

Sliepen, Kwinten ^{[1
]}

Ketas, Thomas J. ^{[7
]}

Pugach, Pavel ^{[7
]}

Yasmeen, Anila ^{[7
]}

Cottrell, Christopher A. ^{[2
,3
]}

Torres, Jonathan L. ^{[2
,3
]}

Vavourakis, Charlotte D. ^{[8
]}

van Gils, Marit J. ^{[1
]}

LaBranche, Celia ^{[9
]}

Montefiori, David C. ^{[9
]}

Desaire, Heather ^{[6
]}

Crispin, Max ^{[5
]}

Klasse, Per Johan ^{[7
]}

Lee, Kelly K. ^{[4
]}

Moore, John P. ^{[7
]}

Ward, Andrew B. ^{[2
,3
]}

Wilson, Ian A. ^{[2
,3
,10
]}

Sanders, Rogier W. ^{[1
,7
]}

机构：

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

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

[3] Scripps Res Inst, CAVD, La Jolla, CA 92037 USA

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

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

[6] Univ Kansas, Dept Chem, Lawrence, KS 66047 USA

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

[8] Univ Amsterdam, Inst Biodivers & Ecosyst Dynam, Dept Freshwater & Marine Ecol, Microbial Syst Ecol, NL-1098 XH Amsterdam, Netherlands

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

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

[11] Hosp Sick Children, Program Mol Med, Res Inst, Toronto, ON M5G 0A4, Canada

[12] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada

[13] Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada

[14] Amgen Inc, Dept Therapeut Discovery, Thousand Oaks, CA 92320 USA

来源：

CELL REPORTS | 2017年 / 20卷 / 08期

基金：

欧洲研究理事会;

关键词：

BROADLY NEUTRALIZING ANTIBODIES; CRYO-EM STRUCTURE; GLYCOPROTEIN COMPLEX; DISULFIDE BONDS; GLYCOSYLATION; TARGET;

D O I：

10.1016/j.celrep.2017.07.077

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The production of native-like recombinant versions of the HIV-1 envelope glycoprotein (Env) trimer requires overcoming the natural flexibility and instability of the complex. The engineered BG505 SOSIP. 664 trimer mimics the structure and antigenicity of native Env. Here, we describe how the introduction of new disulfide bonds between the glycoprotein (gp) 120 and gp41 subunits of SOSIP trimers of the BG505 and other genotypes improves their stability and antigenicity, reduces their conformational flexibility, and helps maintain them in the unliganded conformation. The resulting next-generation SOSIP. v5 trimers induce strong autologous tier-2 neutralizing antibody (NAb) responses in rabbits. In addition, the BG505 SOSIP. v6 trimers induced weak heterologousNAbresponses against a subset of tier-2 viruses that were not elicited by the prototype BG505 SOSIP. 664. These stabilization methods can be applied to trimers from multiple genotypes as components of multivalent vaccines aimed at inducing broadly NAbs (bNAbs).

引用

页码：1805 / 1817

页数：13

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