乙型肝炎病毒preS1受体结合域中的两个关键中和表位的鉴定

StephenW

Identification of Two Critical Neutralizing Epitopes in the Receptor Binding Domain of Hepatitis B Virus preS1
Keigo Yato  1   2 , Taishi Onodera  3 , Mami Matsuda  1 , Saya Moriyama  3 , Akira Fujimoto  4 , Koichi Watashi  1 , Hideki Aizaki  1 , Tomohisa Tanaka  5 , Kohji Moriishi  5 , Hironori Nishitsuji  6 , Kunitada Shimotohno  7 , Koji Tamura  2 , Yoshimasa Takahashi  3 , Takaji Wakita  1 , Masamichi Muramatsu  1 , Takanobu Kato  1 , Ryosuke Suzuki  4   2
Affiliations
Affiliations

    1
    Department of Virology II, National Institute of Infectious Diseases.
    2
    Department of Biological Science and Technology, Tokyo University of Science.
    3
    Department of Immunology, National Institute of Infectious Diseases.
    4
    Department of Virology II, National Institute of Infectious Diseases [email protected].
    5
    Department of Microbiology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, University of Yamanashi.
    6
    Department of Virology and Parasitology, Fujita Health University School of Medicine.
    7
    Genome Medical Sciences Project, National Center for Global Health and Medicine.

    PMID: 33298539 DOI: 10.1128/JVI.01680-20

Abstract

Hepatitis B virus (HBV) infection is a major public health problem. Human hepatocytes are infected with HBV via binding between the preS1 region in the large envelope protein of HBV and sodium taurocholate cotransporting polypeptide. Although several monoclonal antibodies (MAbs) that recognize the receptor binding domain in preS1 and neutralize HBV infection have been isolated, details of neutralizing epitopes are not understood. In this study, we generated 13 MAbs targeting the preS1 receptor binding domain from preS1-specific memory B cells derived from DNA immunized mice. The MAbs were classified into three groups according to the epitope regions, designated epitopes I-III. A virus neutralization assay revealed that MAbs recognizing epitopes I and III neutralized HBV infection, suggesting that these domains are critical epitopes for viral neutralization. In addition, a neutralization assay against multiple genotypes of HBV revealed that epitope I is a semi-pangenotypic neutralizing epitope, whereas epitope III is a genotype-specific epitope. We also showed that neutralizing MAbs against preS1 could neutralize HBV bearing vaccine-induced escape mutation. These findings provide insight into novel immunoprophylaxis for the prevention and treatment of HBV infection.IMPORTANCE The HBV preS1 2-47 aa region (preS1/2-47) is essential for virus binding with sodium taurocholate cotransporting polypeptide. Several MAbs targeting preS1/2-47 have been reported to neutralize HBV infection; however, which region in preS1/2-47 contains the critical neutralizing epitope for HBV infection is unclear. Here, we generated several MAbs targeting preS1/2-47 and found that MAbs recognizing the N- or C-terminus of preS1/2-47 remarkably neutralized HBV infection. We further confirmed the neutralizing activity of anti-preS1 MAbs against HBV with vaccine escape mutation. These data clarified the relationship between the antibody epitope and the virus neutralizing activity and also suggested the potential ability of a vaccine antigen containing the preS1 region to overcome the weakness of current HB vaccines comprising the small S protein.

Copyright © 2020 American Society for Microbiology.

StephenW

乙型肝炎病毒preS1受体结合域中的两个关键中和表位的鉴定
藤井圭吾1 2，大野小野太郎3，松田真美1，森山早矢3，藤本昭4，渡边晃一1，荒木秀树1，田中智久5，森井孝司5，西田浩典6，国田下本彦7，田村浩二2，吉岛平高桥3，高田和司1，村松正一1，加藤隆信1，铃木亮辅4 2
隶属关系
隶属关系

    1个
    国立传染病研究所病毒学系II。
    2
    东京科技大学生物科学与技术系。
    3
    国立传染病研究所免疫学系。
    4
    国立传染病研究所病毒学系[email protected]。
    5
    山梨大学医学系微生物学研究科，跨学科研究科。
    6
    藤田卫生大学医学院病毒与寄生虫学系。
    7
    国家全球健康与医学中心基因组医学科学项目。

    PMID：33298539 DOI：10.1128 / JVI.01680-20

抽象

乙型肝炎病毒（HBV）感染是主要的公共卫生问题。人肝细胞通过HBV大包膜蛋白中的preS1区与牛磺胆酸钠共转运多肽之间的结合而感染HBV。尽管已经分离了几种识别preS1中受体结合结构域并中和HBV感染的单克隆抗体（MAb），但尚不了解中和表位的细节。在这项研究中，我们从DNA免疫小鼠的preS1特异性记忆B细胞中产生了针对preS1受体结合结构域的13种单抗。根据表位区域将单克隆抗体分为三类，称为表位I-III。病毒中和试验表明，识别表位I和III的单克隆抗体可中和HBV感染，这表明这些域是病毒中和的关键表位。此外，针对多种基因型HBV的中和试验显示，表位I是半泛基因型中和表位，而表位III是基因型特异性表位。我们还表明，针对preS1的中和单克隆抗体可以中和带有疫苗诱导的逃逸突变的HBV。这些发现为预防和治疗HBV感染的新型免疫预防提供了见识。重要事项HBV preS1 2-47 aa区域（preS1 / 2-47）对于与牛磺胆酸钠共转运多肽结合病毒至关重要。据报道，有几种靶向preS1 / 2-47的单克隆抗体可中和HBV感染。但是，尚不清楚preS1 / 2-47中的哪个区域包含用于HBV感染的关键中和表位。在这里，我们生成了几种针对preS1 / 2-47的单克隆抗体，发现识别preS1 / 2-47的N或C端的单克隆抗体显着中和了HBV感染。我们进一步证实了抗preS1 MAb对具有疫苗逃逸突变的HBV的中和活性。这些数据阐明了抗体表位与病毒中和活​​性之间的关系，并且还暗示了含有preS1区的疫苗抗原克服现有的包含小S蛋白的HB疫苗的弱点的潜在能力。

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