Computational Design of Epitope-Scaffolds Allows Induction of Antibodies Specific for a Poorly Immunogenic HIV Vaccine Epitope

被引：171

作者：

Correia, Bruno E. ^{[1
,2
]}

Ban, Yih-En Andrew ^{[1
]}

Holmes, Margaret A. ^{[3
]}

Xu, Hengyu ^{[3
]}

Ellingson, Katharine ^{[4
]}

Kraft, Zane ^{[4
]}

Carrico, Chris ^{[1
]}

Boni, Erica ^{[3
]}

Sather, D. Noah ^{[4
]}

Zenobia, Camille ^{[3
]}

Burke, Katherine Y. ^{[3
]}

Bradley-Hewitt, Tyler ^{[3
]}

Bruhn-Johannsen, Jessica F. ^{[3
]}

Kalyuzhniy, Oleksandr ^{[1
]}

Baker, David ^{[1
]}

Strong, Roland K. ^{[3
]}

Stamatatos, Leonidas ^{[4
,5
]}

Schief, William R. ^{[1
]}

机构：

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

[2] Univ Nova Lisboa, Inst Tecnol Quim & Biol, P-2780157 Oeiras, Portugal

[3] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA

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

[5] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA

来源：

STRUCTURE | 2010年 / 18卷 / 09期

关键词：

PROXIMAL EXTERNAL REGION; NEUTRALIZING ANTIBODIES; VIRUS; MEMBRANE; GP41; RECOGNITION; PARTICLES; PROGRAM; PANEL; SITE;

D O I：

10.1016/j.str.2010.06.010

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：

Broadly cross-reactive monoclonal antibodies define epitopes for vaccine development against HIV and other highly mutable viruses. Crystal structures are available for several such antibody-epitope complexes, but methods are needed to translate that structural information into immunogens that re-elicit similar antibodies. We describe a general computational method to design epitope-scaffolds in which contiguous structural epitopes are transplanted to scaffold proteins for conformational stabilization and immune presentation. Epitope-scaffolds designed for the poorly immunogenic but conserved HIV epitope 4E10 exhibited high epitope structural mimicry, bound with higher affinities to monoclonal antibody (mAb) 4E10 than the cognate peptide, and inhibited HIV neutralization by HIV+ sera. Rabbit immunization with an epitope-scaffold induced antibodies with structural specificity highly similar to mAb 4E10, an important advance toward elicitation of neutralizing activity. The results demonstrate that computationally designed epitope-scaffolds are valuable as structure-specific serological reagents and as immunogens to elicit antibodies with predetermined structural specificity.

引用

页码：1116 / 1126

页数：11

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