基于病毒不可或缺，保守性和HLA结合强度的发现和选择用于

StephenW

Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength
Monique T. A. de Beijer, Diahann T. S. L. Jansen, Yingying Dou, Wim J. E. van Esch, Juk Yee Mok, Mariëlle J. P. Maas, Giso Brasser, Robert A. de Man, Andrea M. Woltman, Sonja I. Buschow
J.-H. James Ou, Editor
DOI: 10.1128/JVI.01663-19

    ArticleFigures & DataInfo & Metrics
    PDF

ABSTRACT

Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Pol-derived reported epitopes with functional association and high conservation. We subsequently predicted novel HLA-binding peptides for 6 HLA supertypes prevalent in HBV-infected patients. Potential epitopes expected to be the least prone to immune escape were subjected to a state-of-the-art in vitro assay to validate their HLA-binding capacity. Using this method, a total of 13 HLA binders derived from HBx and 33 binders from Pol were identified across HLA types. Subsequently, we demonstrated interferon gamma (IFN-γ) production in response to 5 of the novel HBx-derived binders and 17 of the novel Pol-derived binders. In addition, we validated several infrequently described epitopes. Collectively, these results specify a set of highly potent T cell epitopes that represent a valuable resource for future HBV immunotherapy design.

IMPORTANCE Multiple HBV-derived T cell epitopes have been reported, which can be useful in a therapeutic vaccination strategy. However, these epitopes are largely restricted to HLA-A*02, which is not dominantly expressed in populations with high HBV prevalence. Thus, current epitopes are falling short in the development of a global immunotherapeutic approach. Therefore, we aimed to identify novel epitopes for 6 HLA supertypes most prevalent in the infected population. Moreover, established epitopes might not all be equally effective as they can be subject to different levels of immune escape. It is therefore important to identify targets that are crucial in viral replication and conserved in the majority of the infected population. Here, we applied a stringent selection procedure to compose a combined overview of existing and novel HBV-derived T cell epitopes most promising for viral eradication. This set of T cell epitopes now lays the basis for the development of globally effective HBV antigen-specific immunotherapies.

StephenW

基于病毒不可或缺，保守性和HLA结合强度的发现和选择用于全球免疫治疗的乙肝病毒衍生的T细胞表位
Monique T.A. de Beijer，Diahann T.L. Jansen，窦颖颖，Wim J.E. van Esch，Juk Yee Mok，MariëlleJ.P.Maas，Giso Brasser，Robert A.de Man，Andrea M.Woltman，Sonja I.Buschow
J.-H.欧文（James Ou），编辑
DOI：10.1128 / JVI.01663-19

    文章图形与数据信息与度量
    PDF格式

抽象

免疫疗法是治疗慢性乙型肝炎病毒（HBV）感染的一种有吸引力的选择。 HBV蛋白聚合酶（Pol）和HBx对于抗原特异性免疫治疗特别感兴趣，因为它们对于病毒复制至关重要，并且与病毒控制（Pol）相关，或者在病毒DNA整合（HBx）时仍会表达。在这里，我们对所有当前描述的HBx和Pol衍生的表位序列进行了评分，以了解所有HBV基因型的病毒不可缺少性和保守性。这样就产生了7个HBx衍生和26个Pol衍生的表位，具有功能关联和高度保守性。我们随后预测了在HBV感染患者中流行的6种HLA超型的新型HLA结合肽。对预期最不容易发生免疫逃逸的潜在表位进行了最新的体外测定，以验证其HLA结合能力。使用此方法，在所有HLA类型中共鉴定了13种HBx衍生的HLA粘合剂和33种Pol衍生的粘合剂。随后，我们证明了干扰素γ（IFN-γ）的产生对5种新的HBx衍生粘合剂和17种新的Pol衍生粘合剂的响应。此外，我们验证了几种不常见的表位。总而言之，这些结果表明了一组高效的T细胞表位，代表了未来HBV免疫疗法设计的宝贵资源。

重要事项已报道了多个HBV衍生的T细胞表位，可用于治疗性疫苗接种策略。但是，这些表位在很大程度上限于HLA-A * 02，在HBV流行率高的人群中并未主要表达。因此，在全球免疫治疗方法的发展中，当前的表位不足。因此，我们旨在为感染人群中最普遍的6种HLA超型确定新的表位。此外，已建立的表位可能并非都具有同等效力，因为它们可能会遭受不同程度的免疫逃逸。因此，重要的是确定在病毒复制中至关重要且在大多数感染人群中均保守的靶标。在这里，我们应用了严格的选择程序，对最有希望消除病毒的现有和新颖的HBV衍生T细胞表位进行了综合概述。现在，这组T细胞表位为开发全球有效的HBV抗原特异性免疫疗法奠定了基础。

StephenW

https://jvi.asm.org/content/jvi/94/7/e01663-19.full.pdf