Structural analysis of a dengue cross-reactive antibody complexed with envelope domain III reveals the molecular basis of cross-reactivity.
Structural analysis of a dengue cross-reactive antibody complexed with envelope domain III reveals the molecular basis of cross-reactivity.
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DOI：
10.4049/jimmunol.1200227
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发表时间：
2012-05-15
期刊：
影响因子：
--
通讯作者：
Screaton GR
中科院分区：
文献类型：
--
作者：
Midgley CM;Flanagan A;Tran HB;Dejnirattisai W;Chawansuntati K;Jumnainsong A;Wongwiwat W;Duangchinda T;Mongkolsapaya J;Grimes JM;Screaton GR
在热带和亚热带国家，登革热病毒感染仍在以惊人的速度增加，因此需要登革热疫苗。虽然产生针对登革热病毒的抗体反应相对容易，但低亲和力或低浓度的抗体可能增强Fc受体承载细胞的感染，具有临床影响，对疫苗生产构成挑战。在本文中，我们报告了一种单克隆抗体2H12的特性，它对登革热病毒组的所有四种血清型都有交叉反应。测定了三种登革热血清型包膜蛋白结构域III复合物中2H12-Fab的晶体结构。2H12结合在成熟病毒粒子中难以接近的包膜蛋白结构域III的高度保守的AB环上。不同登革热血清型和菌株对2H12的中和作用不同；特别是2型登革热血清未被中和。由于2H12结合表位是保守的，这种中和的变化突出了登革热血清型之间的差异，并表明抗体结合必须在病毒中发生显着的构象变化。令人惊讶的是，2H12几乎没有促进感染的增强。这些数据为了解抗体中和和增强感染提供了结构基础，这对未来登革热疫苗的开发至关重要。
Dengue virus infections are still increasing at an alarming rate in tropical and subtropical countries underlying the need for a dengue vaccine. Although it is relatively easy to generate antibody responses to dengue virus, low avidity or low concentrations of antibody may enhance infection of Fc receptor-bearing cells with clinical impact, posing a challenge to vaccine production. In this paper we report the characterization of a monoclonal antibody, 2H12, which is cross-reactive to all four serotypes in the dengue virus group. Crystal structures of 2H12-Fab in complex with domain III of the envelope protein from three dengue serotypes have been determined. 2H12 binds to the highly conserved AB loop of domain III of the envelope protein that is poorly accessible in the mature virion. 2H12 neutralization varied between dengue serotypes and strains; in particular, dengue serotype 2 was not neutralized. As the 2H12 binding epitope was conserved, this variation in neutralization highlights differences between dengue serotypes and suggests that significant conformational changes in the virus must take place for antibody binding. Surprisingly, 2H12 facilitated little or no enhancement of infection. These data provide a structural basis for understanding antibody neutralization and enhancement of infection, which is crucial for the development of future dengue vaccines.
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影响因子：
3.7
作者：
Hiramatsu, K;Tadano, M;Lai, CJ
通讯作者：
Lai, CJ
影响因子：
6.7
作者：
Balsitis SJ;Williams KL;Lachica R;Flores D;Kyle JL;Mehlhop E;Johnson S;Diamond MS;Beatty PR;Harris E
通讯作者：
Harris E
DOI：
10.1073/pnas.0703498104
发表时间：
2007-05-29
影响因子：
11.1
作者：
Goncalvez, Ana P.;Engle, Ronald E.;Lai, Ching-Juh
通讯作者：
Lai, Ching-Juh
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.7
作者：
Bernardo, Lidice;Hermida, Lisset;Guzman, Maria G.
通讯作者：
Guzman, Maria G.