Wong Yee Hwa, Goh Boon Chong, Lim She Yah, Teo En Wei, Lim Angeline P C, Dedon Pete C, Hanson Brendon J, MacAry Paul A, Lescar Julien
Nanyang Institute for Structural Biology, School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
Singapore-MIT Alliance for Research and Technology, Singapore, Singapore.
J Virol. 2017 Aug 10;91(17). doi: 10.1128/JVI.00406-17. Print 2017 Sep 1.
A detailed understanding of the fine specificity of serotype-specific human antibodies is vital for the development and evaluation of new vaccines for pathogenic flaviviruses such as dengue virus (DENV) and Zika virus. In this study, we thoroughly characterize the structural footprint of an anti-idiotype antibody (E1) specific for a potent, fully human DENV serotype 1-specific antibody, termed HM14c10, derived from a recovered patient. The crystal structure at a resolution of 2.5 Å of a complex between the Fab fragments of E1 and HM14c10 provides the first detailed molecular comparison of an anti-idiotype paratope specific for a human antibody with its analogous epitope, a discontinuous quaternary structure located at the surface of the viral particle that spans adjacent envelope (E) proteins. This comparison reveals that the footprints left by E1 and E on HM14c10 largely overlap, explaining why the formation of binary complexes is mutually exclusive. Structural mimicry of the DENV E epitope by the E1 combining site is achieved via the formation of numerous interactions with heavy chain complementarity domain regions (CDRs) of HM14c10, while fewer interactions are observed with its light chain than for the E protein. We show that E1 can be utilized to detect HM14c10-like antibodies in sera from patients who recovered from DENV-1, infection suggesting that this is a public (common) idiotype. These data demonstrate the utility of employing an anti-idiotype antibody to monitor a patient's specific immune responses and suggest routes for the improvement of E "mimicry" by E1 by increasing its recognition of the Fab HM14c10 light chain CDRs. A chimeric yellow fever-dengue live-attenuated tetravalent vaccine is now being marketed. Dengue remains a significant public health problem, because protection conferred by this vaccine against the four circulating serotypes is uneven. Reliable tools must be developed to measure the immune responses of individuals exposed to DENV either via viral infection or through vaccination. Anti-idiotypic antibodies provide precision tools for analyzing the pharmacokinetics of antibodies in an immune response and also for measuring the amount of circulating anti-infective therapeutic antibodies. Here, we characterize how an anti-idiotypic antibody (E1) binds antibody HM14c10, which potently neutralizes DENV serotype 1. We report the crystal structure at a resolution of 2.5 Å of a complex between the Fab fragments of E1 and HM14c10 and provide the first detailed molecular comparison between the anti-idiotype surface and its analogous epitope located at the surface of the dengue virus particle.
深入了解血清型特异性人类抗体的精细特异性，对于开发和评估针对登革热病毒（DENV）和寨卡病毒等致病性黄病毒的新型疫苗至关重要。在本研究中，我们全面表征了一种抗独特型抗体（E1）的结构特征，该抗体特异性针对一种源自康复患者的强效、全人源DENV 1型特异性抗体，称为HM14c10。E1和HM14c10的Fab片段复合物分辨率为2.5 Å的晶体结构，首次详细比较了针对人类抗体的抗独特型互补决定区与其类似表位，该表位是位于病毒颗粒表面跨越相邻包膜（E）蛋白的不连续四级结构。这种比较表明，E1和E在HM14c10上留下的印记大部分重叠，解释了为何二元复合物的形成相互排斥。E1结合位点对DENV E表位的结构模拟是通过与HM14c10的重链互补决定区（CDR）形成众多相互作用实现的，而与轻链的相互作用比与E蛋白的少。我们表明，E1可用于检测DENV-1感染康复患者血清中类似HM14c10的抗体，表明这是一种公共（常见）独特型。这些数据证明了使用抗独特型抗体监测患者特异性免疫反应的实用性，并通过增加其对Fab HM14c10轻链CDR的识别，为改善E1对E的“模拟”提供了途径。一种嵌合黄热病 - 登革热减毒活四价疫苗目前正在上市。登革热仍然是一个重大的公共卫生问题，因为这种疫苗对四种流行血清型提供的保护并不均匀。必须开发可靠的工具来测量通过病毒感染或疫苗接种接触DENV的个体的免疫反应。抗独特型抗体为分析免疫反应中抗体的药代动力学以及测量循环中的抗感染治疗性抗体量提供了精确工具。在此，我们表征了抗独特型抗体（E1）如何结合能有效中和DENV 1型的抗体HM14c10。我们报告了E1和HM14c10的Fab片段复合物分辨率为2.5 Å的晶体结构，并首次详细比较了抗独特型表面与其位于登革热病毒颗粒表面的类似表位。
