Escape of Hepatitis C Virus from Epitope I Neutralization Increases Sensitivity of Other Neutralization Epitopes
Escape of Hepatitis C Virus from Epitope I Neutralization Increases Sensitivity of Other Neutralization Epitopes
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DOI：
10.1128/jvi.02066-17
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发表时间：
2018-05-01
影响因子：
5.4
通讯作者：
Drummer, Heidi E.
中科院分区：
文献类型：
--
作者：
Gu, Jun;Hardy, Joshua;Drummer, Heidi E.
丙型肝炎病毒（HCV） E2糖蛋白是中和抗体（nAb）应答的主要靶点，具有多种类型特异性和广泛中和抗体（bnAb）表位。412- 423区域可以产生阻断与细胞表面受体CD81相互作用的bnAbs，对多种HCV基因型具有活性。在这项研究中，我们揭示了啮齿动物单克隆抗体24 （MAb24）的结构，该抗体具有广泛的接触区域，指向跨越412至423区域的肽。MAb24-peptide 412-to-423复合物的晶体结构揭示了与人单克隆抗体HCV1和啮齿动物单克隆抗体AP33所观察到的肽发夹高度相似的paratope，但观察角度不同。在病毒生长实验中，我们证明了三种不同的基因型2a病毒群体通过N415D、N417S和N415D/H386R突变获得对MAb24的抗性。重要的是，mab24耐药病毒对大多数针对412- 423区表位的bnAbs以及E2和E1E2复合物内的其他抗原决定因子的敏感性显著增加。这项研究表明，N415的修饰导致糖蛋白结构的全局变化，增加了其被其他抗体中和的脆弱性。这一发现表明，在对病毒感染的抗体反应中，在412- 423区域获得逃逸突变使病毒更容易被nab的其他特异性中和，有效地降低了病毒的免疫适应性。需要一种对412- 423区和E2至少一个其他区域产生多特异性体液免疫的HCV疫苗。了解抗体如何中和丙型肝炎病毒（HCV）对疫苗开发至关重要。这项研究首次揭示，当HCV对针对E2的412- 423区域的一类主要bnAb产生耐药性时，这将导致对大多数其他bnAb特异性中和的敏感性增加。因此，预防HCV感染的疫苗应该产生针对E2的412- 423区域和病毒糖蛋白内其他bnAb表位的bnAb抗体。
The hepatitis C virus (HCV) E2 glycoprotein is a major target of the neutralizing antibody (nAb) response, with multiple type-specific and broadly neutralizing antibody (bnAb) epitopes identified. The 412-to-423 region can generate bnAbs that block interaction with the cell surface receptor CD81, with activity toward multiple HCV genotypes. In this study, we reveal the structure of rodent monoclonal antibody 24 (MAb24) with an extensive contact area toward a peptide spanning the 412-to-423 region. The crystal structure of the MAb24-peptide 412-to-423 complex reveals the paratope bound to a peptide hairpin highly similar to that observed with human MAb HCV1 and rodent MAb AP33, but with a different angle of approach. In viral outgrowth experiments, we demonstrated three distinct genotype 2a viral populations that acquired resistance to MAb24 via N415D, N417S, and N415D/H386R mutations. Importantly, the MAb24-resistant viruses exhibited significant increases in sensitivity to the majority of bnAbs directed to epitopes within the 412-to-423 region and in additional antigenic determinants located within E2 and the E1E2 complex. This study suggests that modification of N415 causes a global change in glycoprotein structure that increases its vulnerability to neutralization by other antibodies. This finding suggests that in the context of an antibody response to viral infection, acquisition of escape mutations in the 412-to-423 region renders the virus more susceptible to neutralization by other specificities of nAbs, effectively reducing the immunological fitness of the virus. A vaccine for HCV that generates polyspecific humoral immunity with specificity for the 412-to-423 region and at least one other region of E2 is desirable.IMPORTANCE Understanding how antibodies neutralize hepatitis C virus (HCV) is essential for vaccine development. This study reveals for the first time that when HCV develops resistance to a major class of bnAbs targeting the 412-to-423 region of E2, this results in a concomitant increase in sensitivity to neutralization by a majority of other bnAb specificities. Vaccines for the prevention of HCV infection should therefore generate bnAbs directed toward the 412-to-423 region of E2 and additional bnAb epitopes within the viral glycoproteins.