Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors

被引：625

作者：

Jardine, Joseph ^{[1
,2
,3
,4
]}

Julien, Jean-Philippe ^{[2
,3
,5
]}

Menis, Sergey ^{[1
,2
,3
,4
]}

Ota, Takayuki ^{[1
]}

Kalyuzhniy, Oleksandr ^{[1
,2
,3
,4
]}

McGuire, Andrew ^{[6
]}

Sok, Devin ^{[1
,2
,3
]}

Huang, Po-Ssu ^{[4
]}

MacPherson, Skye ^{[1
,2
,3
,4
]}

Jones, Meaghan ^{[1
,2
,4
]}

Nieusma, Travis ^{[2
,3
,5
]}

Mathison, John ^{[1
]}

Baker, David ^{[4
]}

Ward, Andrew B. ^{[2
,3
,5
]}

Burton, Dennis R. ^{[1
,2
,3
,7
]}

Stamatatos, Leonidas ^{[6
,8
]}

Nemazee, David ^{[1
]}

Wilson, Ian A. ^{[2
,3
,5
,9
]}

Schief, William R. ^{[1
,2
,3
,4
]}

机构：

[1] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Int AIDS Vaccine Initiat Neutralizing Antibody Ct, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Ctr HIV AIDS Vaccine Immunol & Immunogen Discover, La Jolla, CA 92037 USA

[4] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[5] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[6] Seattle Biomed Res Inst, Seattle, WA 98109 USA

[7] Ragon Inst Massachusetts Gen Hosp Massachusetts I, Cambridge, MA 02129 USA

[8] Univ Washington, Dept Global Hlth, Seattle, WA 98109 USA

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

来源：

SCIENCE | 2013年 / 340卷 / 6133期

基金：

加拿大健康研究院;

关键词：

STRUCTURAL BASIS; ANTIBODIES; POTENT; BROAD; NEUTRALIZATION; VIRUSES; ENV;

D O I：

10.1126/science.1234150

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Vaccine development to induce broadly neutralizing antibodies (bNAbs) against HIV-1 is a global health priority. Potent VRC01-class bNAbs against the CD4 binding site of HIV gp120 have been isolated from HIV-1-infected individuals; however, such bNAbs have not been induced by vaccination. Wild-type gp120 proteins lack detectable affinity for predicted germline precursors of VRC01-class bNAbs, making them poor immunogens to prime a VRC01-class response. We employed computation-guided, in vitro screening to engineer a germline-targeting gp120 outer domain immunogen that binds to multiple VRC01-class bNAbs and germline precursors, and elucidated germline binding crystallographically. When multimerized on nanoparticles, this immunogen (eOD-GT6) activates germline and mature VRC01-class B cells. Thus, eOD-GT6 nanoparticles have promise as a vaccine prime. In principle, germline-targeting strategies could be applied to other epitopes and pathogens.

引用

页码：711 / 716

页数：6

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