Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress.
Therapeutic alphavirus cross-reactive E1 human antibodies inhibit viral egress.
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DOI：
10.1016/j.cell.2021.07.033
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发表时间：
2021-08-19
期刊：
影响因子：
64.5
通讯作者：
Crowe JE Jr
中科院分区：
文献类型：
--
作者：
Williamson LE;Reeder KM;Bailey K;Tran MH;Roy V;Fouch ME;Kose N;Trivette A;Nargi RS;Winkler ES;Kim AS;Gainza C;Rodriguez J;Armstrong E;Sutton RE;Reidy J;Carnahan RH;McDonald WH;Schoeder CT;Klimstra WB;Davidson E;Doranz BJ;Alter G;Meiler J;Schey KL;Julander JG;Diamond MS;Crowe JE Jr
甲型病毒会导致严重的关节炎或脑炎疾病。E1结构糖蛋白在这些病毒中高度保守，并介导病毒与宿主细胞的融合。然而，对E1蛋白的抗体反应在免疫中的作用还知之甚少。我们从自然感染EEEV的幸存者中分离出对甲型病毒(从东部马脑炎病毒(EEEV)特异性到甲型病毒交叉反应)具有不同识别模式的E1特异性人类单抗(MAbs)。抗体结合模式和表位映射实验确定了E1反应的差异，这是基于通过pH依赖的机制暴露在糖蛋白上的表位或在病毒出口之前呈现在细胞表面上的。这些单抗的体内疗效与体外抑制病毒出口的效力一致，不需要Fc介导的效应器功能来对抗EEEV皮下攻击。这些研究揭示了针对甲型病毒E1蛋白的广泛和保护性抗体反应的分子基础。从自然东部马脑炎病毒感染幸存者那里获得的针对隐蔽表位的广谱反应的甲型病毒E1抗体在体外抑制病毒出口，并保护小鼠免受脑炎(东部马脑炎)和关节炎(基孔肯雅)甲型病毒的感染。
Alphaviruses cause severe arthritogenic or encephalitic disease. The E1 structural glycoprotein is highly conserved in these viruses and mediates viral fusion with host cells. However, the role of antibody responses to the E1 protein in immunity is poorly understood. We isolated E1-specific human monoclonal antibodies (mAbs) with diverse patterns of recognition for alphaviruses (ranging from Eastern equine encephalitis virus (EEEV)-specific to alphavirus cross-reactive) from survivors of natural EEEV infection. Antibody binding patterns and epitope mapping experiments identified differences in E1 reactivity based on exposure of epitopes on the glycoprotein through pH-dependent mechanisms or presentation on the cell surface prior to virus egress. Therapeutic efficacy in vivo of these mAbs corresponded with potency of virus egress inhibition in vitro and did not require Fc-mediated effector functions for treatment against subcutaneous EEEV challenge. These studies reveal the molecular basis for broad and protective antibody responses to alphavirus E1 proteins. Broadly reactive alphavirus E1 antibodies to cryptic epitopes obtained from survivors of natural Eastern equine encephalitis virus infection inhibit virus egress in vitro and protect against infection by encephalitic (Eastern equine encephalitis) and arthritogenic (chikungunya) alphaviruses in mice.
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影响因子：
64.5
作者：
FULLER, SD;BERRIMAN, JA;GOWEN, BE
通讯作者：
GOWEN, BE
DOI：
10.1126/science.aaa8651
发表时间：
2015-07-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fibriansah G;Ibarra KD;Ng TS;Smith SA;Tan JL;Lim XN;Ooi JS;Kostyuchenko VA;Wang J;de Silva AM;Harris E;Crowe JE Jr;Lok SM
通讯作者：
Lok SM
影响因子：
2.2
作者：
Karsten, Christina B.;Mehta, Nickita;Alter, Galit
通讯作者：
Alter, Galit
影响因子：
--
作者：
Giudicelli, Veronique;Brochet, Xavier;Lefranc, Marie-Paule
通讯作者：
Lefranc, Marie-Paule
影响因子：
5.4
作者：
Ahn, A;Klimjack, MR;Kielian, M
通讯作者：
Kielian, M