Structural basis of respiratory syncytial virus subtype-dependent neutralization by an antibody targeting the fusion glycoprotein.
Structural basis of respiratory syncytial virus subtype-dependent neutralization by an antibody targeting the fusion glycoprotein.
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靶向融合糖蛋白的抗体对呼吸道合胞病毒亚型依赖性中和的结构基础
DOI：
10.1038/s41467-017-01858-w
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发表时间：
2017-11-30
影响因子：
16.6
通讯作者：
Graham BS
中科院分区：
文献类型：
--
作者：
Tian D;Battles MB;Moin SM;Chen M;Modjarrad K;Kumar A;Kanekiyo M;Graepel KW;Taher NM;Hotard AL;Moore ML;Zhao M;Zheng ZZ;Xia NS;McLellan JS;Graham BS
目前还没有获得许可的呼吸道合胞病毒（RSV）疫苗，使用抗体帕利珠单抗进行被动预防仅限于高危婴儿。最近分离的抗体5C4和D25实质上比帕利珠单抗更有效，并且D25的衍生物处于临床试验中。在这里，我们表明，不像D25，5C4优先中和亚型A病毒。与RSV融合（F）蛋白结合的5C4的晶体结构揭示了5C4的总体结合模式与D25的结合模式相似，但它们的接近角度基本上不同。突变和病毒学研究表明，RSV F残基201主要负责5C4的亚型特异性。这些结果提高了我们对亚型特异性免疫和下一代抗体的中和宽度要求的理解，从而有助于设计广泛保护性RSV疫苗。预防呼吸道合胞病毒（RSV）疾病的单克隆抗体正在开发中，但交叉亚型中和的分子要求尚不清楚。在此，作者表明RSV融合蛋白中的残基201决定临床相关单克隆抗体5C4的亚型特异性中和。
A licensed vaccine for respiratory syncytial virus (RSV) is unavailable, and passive prophylaxis with the antibody palivizumab is restricted to high-risk infants. Recently isolated antibodies 5C4 and D25 are substantially more potent than palivizumab, and a derivative of D25 is in clinical trials. Here we show that unlike D25, 5C4 preferentially neutralizes subtype A viruses. The crystal structure of 5C4 bound to the RSV fusion (F) protein reveals that the overall binding mode of 5C4 is similar to that of D25, but their angles of approach are substantially different. Mutagenesis and virological studies demonstrate that RSV F residue 201 is largely responsible for the subtype specificity of 5C4. These results improve our understanding of subtype-specific immunity and the neutralization breadth requirements of next-generation antibodies, and thereby contribute to the design of broadly protective RSV vaccines. Monoclonal antibodies to prevent respiratory syncytial virus (RSV) disease are under development, but the molecular requirements for cross-subtype neutralization are unclear. Here, the authors show that residue 201 in RSV fusion protein determines subtype specific neutralization for the clinically-relevant monoclonal antibody, 5C4.
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影响因子：
16.8
作者：
Kong, Leopold;Lee, Jeong Hyun;Doores, Katie J.;Murin, Charles D.;Julien, Jean-Philippe;McBride, Ryan;Liu, Yan;Marozsan, Andre;Cupo, Albert;Klasse, Per-Johan;Hoffenberg, Simon;Caulfield, Michael;King, C. Richter;Hua, Yuanzi;Le, Khoa M.;Khayat, Reza;Deller, Marc C.;Clayton, Thomas;Tien, Henry;Feizi, Ten;Sanders, Rogier W.;Paulson, James C.;Moore, John P.;Stanfield, Robyn L.;Burton, Dennis R.;Ward, Andrew B.;Wilson, Ian A.
通讯作者：
Wilson, Ian A.
影响因子：
16.6
作者：
Krarup A;Truan D;Furmanova-Hollenstein P;Bogaert L;Bouchier P;Bisschop IJM;Widjojoatmodjo MN;Zahn R;Schuitemaker H;McLellan JS;Langedijk JPM
通讯作者：
Langedijk JPM
影响因子：
3.7
作者：
Hotard AL;Shaikh FY;Lee S;Yan D;Teng MN;Plemper RK;Crowe JE Jr;Moore ML
通讯作者：
Moore ML
DOI：
10.1126/science.1234914
发表时间：
2013-05-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McLellan JS;Chen M;Leung S;Graepel KW;Du X;Yang Y;Zhou T;Baxa U;Yasuda E;Beaumont T;Kumar A;Modjarrad K;Zheng Z;Zhao M;Xia N;Kwong PD;Graham BS
通讯作者：
Graham BS
影响因子：
168.9
作者：
Lozano, Rafael;Naghavi, Mohsen;Murray, Christopher J. L.
通讯作者：
Murray, Christopher J. L.