Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins.
Functional convergence of a germline-encoded neutralizing antibody response in rhesus macaques immunized with HCV envelope glycoproteins.
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DOI：
10.1016/j.immuni.2021.02.013
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发表时间：
2021-04-13
期刊：
影响因子：
32.4
通讯作者：
Law M
中科院分区：
文献类型：
--
作者：
Chen F;Tzarum N;Lin X;Giang E;Velázquez-Moctezuma R;Augestad EH;Nagy K;He L;Hernandez M;Fouch ME;Grinyó A;Chavez D;Doranz BJ;Prentoe J;Stanfield RL;Lanford R;Bukh J;Wilson IA;Zhu J;Law M
靶向丙型肝炎病毒（HCV）包膜糖蛋白（Env）E2的人IGHV 1 -69编码的广泛中和抗体（bnAb）对于保护免受HCV感染很重要。IGHV 1 -69直系同源基因VH1.36优先用于从HCV Env免疫的恒河猴（RM）分离的bnAb。在这里，我们研究了通过疫苗接种产生的VH1.36编码的bnAb的遗传、结构和功能特性，并与来自HCV患者的IGHV 1 -69编码的bnAb进行了比较。全局B细胞库分析证实了免疫动物中VH 1.36衍生的B细胞的扩增。大多数E2特异性的VH1.36编码的抗体交叉中和HCV。两个RM bnAb与E2的晶体结构显示，RM bnAb使用与人bnAb相似的分子特征但具有不同的结合模式来接合保守的E2表位。免疫过程中RM抗体库反应的纵向分析表明，VH1.36编码的bnAb具有有限的体细胞超突变的快速谱系发展。我们的研究结果表明，生殖细胞编码的bnAb对HCV Env的反应的功能收敛与人类疫苗接种的影响。人IGHV 1 -69基因优先用于针对HCV感染的广泛中和抗体（bnAb）应答。Chen等人发现猕猴的HCV Env免疫在功能和分子水平上引发类似的VH 1.36 bnAb。灵长类动物中相应种系编码的bnAb应答的功能收敛对HCV疫苗的合理设计和测试具有意义。
Human IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) that target the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection. An IGHV1-69 ortholog gene, VH1.36, is preferentially used for bnAbs isolated from HCV Env-immunized rhesus macaques (RMs). Here we studied the genetic, structural and functional properties of VH1.36-encoded bnAbs generated by vaccination, in comparison to IGHV1-69-encoded bnAbs from HCV patients. Global B cell repertoire analysis confirmed the expansion of VH1.36-derived B cells in immunized animals. Most E2-specific, VH1.36-encoded antibodies cross-neutralized HCV. Crystal structures of two RM bnAbs with E2 revealed that the RM bnAbs engaged conserved E2 epitopes using similar molecular features as human bnAbs but with a different binding mode. Longitudinal analyses of the RM antibody repertoire responses during immunization indicated rapid lineage development of VH1.36-encoded bnAbs with limited somatic hypermutation. Our findings suggest functional convergence of a germline-encoded bnAb response to HCV Env with implications to vaccination in humans. The human IGHV1-69 gene is preferentially utilized in broadly neutralizing antibody (bnAb) responses against HCV infection. Chen et al. discovered that HCV Env immunization of macaques elicited analogous VH1.36 bnAbs on the functional and molecular level. Functional convergence of a corresponding germline-encoded bnAb response within primates has implications for HCV rational vaccine design and testing.
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影响因子：
7.7
作者：
Flyak, Andrew, I;Ruiz, Stormy E.;Bjorkman, Pamela J.
通讯作者：
Bjorkman, Pamela J.
影响因子：
6.7
作者：
Gopal, Radhika;Jackson, Kelli;Law, Mansun
通讯作者：
Law, Mansun
DOI：
10.1007/978-1-4939-8976-8_30
发表时间：
2019-01-01
期刊：
HEPATITIS C VIRUS PROTOCOLS
影响因子：
--
作者：
Bailey, Justin R.;Urbanowicz, Richard A.;Foung, Steven K. H.
通讯作者：
Foung, Steven K. H.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8
作者：
Bailey, Justin R.;Flyak, Andrew I.;Crowe, James E., Jr.
通讯作者：
Crowe, James E., Jr.