Structural Basis for the Shared Neutralization Mechanism of Three Classes of Human Papillomavirus Type 58 Antibodies with Disparate Modes of Binding
Structural Basis for the Shared Neutralization Mechanism of Three Classes of Human Papillomavirus Type 58 Antibodies with Disparate Modes of Binding
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DOI：
10.1128/jvi.01587-20
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发表时间：
2021-04-01
影响因子：
5.4
通讯作者：
Xia, Ningsha
中科院分区：
文献类型：
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作者：
He, Maozhou;Chi, Xin;Xia, Ningsha
人乳头瘤病毒58型（HPV 58）与宫颈癌有关，在世界范围内造成重大的健康负担。尽管商业化的9价HPV疫苗覆盖了HPV 58，但HPV 58完整病毒粒子的结构和分子水平的中和位点尚未完全了解。在这里，我们报告的高分辨率（类似于3.5埃）的完整的HPV 58假病毒（PsV 58）的结构，确定通过使用冷冻电子显微镜（cryo-EM）。通过从一组针对HPV 58的nAb中聚类选择三种代表性中和单克隆抗体（nAb 5G 9、2 H3和A4 B4）。通过分析HPV Fab-衣壳免疫复合物中的空间位阻和对称性错配，我们在PsV 58中提出了三种不同的中和表位，并表明尽管结合存在差异，但这些nAb共享中和机制。这些结果提供了深入了解HPV 58基因型特异性和扩大我们的理解HPV 58中和位点的抗病毒research.IMPORTANCE宫颈癌主要是由于持续感染高危型人乳头瘤病毒（HPV）。HPV 58型（HPV 58）是一种重要的病原体，特别是在亚洲。尽管如此，我们仍然有关于HPV 58的结构和中和表位的有限数据，这使得我们对该病毒感染模式的深入了解更加困难。在这里，我们表明，来自三个不同群体的代表性nAb（5G 9，10 B11，2 H3，5 H2和A4 B4）共享一种中和机制，似乎可以阻止病毒与细胞外基质和细胞表面结合。此外，我们确定nAb通过三种不同的结合模式接合：顶部中心结合（5G 9和10 B11）、顶部边缘结合（2 H3和5 H2）和边缘结合（A4 B4）。我们的工作表明，尽管结合模式存在差异，但针对HPV 58的nAbs具有共同的中和机制。这些结果为HPV 58感染提供了新的见解。
Human papillomavirus type 58 (HPV58) is associated with cervical cancer and poses a significant health burden worldwide. Although the commercial 9-valent HPV vaccine covers HPV58, the structural and molecular-level neutralization sites of the HPV58 complete virion are not fully understood. Here, we report the high-resolution (similar to 3.5-angstrom) structure of the complete HPV58 pseudovirus (PsV58), determined by using cryo-electron microscopy (cryo-EM). Three representative neutralizing monoclonal antibodies (nAbs 5G9, 2H3, and A4B4) were selected through clustering from a panel of nAbs against HPV58. Bypassing the steric hindrance and symmetry mismatch in the HPV Fab-capsid immune complex, we present three different neutralizing epitopes in the PsV58 and show that, despite differences in binding, these nAbs share a neutralization mechanism. These results offer insight into HPV58 genotype specificity and broaden our understanding of HPV58 neutralization sites for antiviral research.IMPORTANCE Cervical cancer primarily results from persistent infection with high-risk types of human papillomavirus (HPV). HPV type 58 (HPV58) is an important causative agent, especially in Asia. Despite this, we still have limited data pertaining to the structural and neutralizing epitopes of HPV58, and this encumbers our in-depth understanding of the virus' mode of infection. Here, we show that representative nAbs (5G9, 10B11, 2H3, 5H2, and A4B4) from three different groups share a neutralization mechanism that appears to prohibit the virus from associating with the extracellular matrix and cell surface. Furthermore, we determined that the nAbs engage via three different binding patterns: top-center binding (5G9 and 10B11), top-fringe binding (2H3 and 5H2), and fringe binding (A4B4). Our work shows that, despite differences in the pattern in binding, nAbs against HPV58 share a neutralization mechanism. These results provide new insight into HPV58 infection.