乙型肝炎病毒特异性 CD4 T 细胞反应将功能性治愈与慢性表面

StephenW

乙型肝炎病毒特异性 CD4 T 细胞反应将功能性治愈与慢性表面抗原 + 感染区分开来
Ruben C Hoogeveen 1、Suzan Dijkstra 2、Lea M Bartsch 2、Hannah Drescher 2、Jasneet Aneja 2、Maxwell P Robidoux 2、James A Cheney 2、Jörg Timm 3、Adam Gehring 4、Paulo Sergio Fonseca de Sousa 5、Lya Ximenez , Luis Baiao Peliganga 6 , Anita Pitts 2 , Fiona Evans Blackburn 2 , André Boonstra 7 , Arthur Y Kim 8 , Lia L Lewis-Ximenez 5 , Georg M Lauer 9
隶属关系
隶属关系

    1
    美国波士顿马萨诸塞州总医院和哈佛医学院肠胃科；荷兰鹿特丹大学医学中心 Erasmus MC 胃肠病学和肝病学系。
    2
    美国波士顿马萨诸塞州总医院和哈佛医学院肠胃科。
    3
    德国杜塞尔多夫大学医院海因里希海涅大学病毒学研究所。
    4
    多伦多肝病中心，多伦多综合医院研究所，大学健康网络，多伦多，安大略省，加拿大；多伦多大学免疫学系，多伦多，安大略省，加拿大。
    5
    奥斯瓦尔多克鲁兹研究所，Fundação Oswaldo Cruz，巴西里约热内卢。
    6
    奥斯瓦尔多克鲁兹研究所，Fundação Oswaldo Cruz，巴西里约热内卢； Faculdade de Medicina da Universidade Agostinho Neto，罗安达，安哥拉； Ministério da Saúde de Angola，罗安达，安哥拉。
    7
    荷兰鹿特丹大学医学中心 Erasmus MC 胃肠病学和肝病学系。
    8
    美国波士顿马萨诸塞州总医院和哈佛医学院传染病科。
    9
    美国波士顿马萨诸塞州总医院和哈佛医学院肠胃科。电子地址：[email protected]。

    PMID：35716846 DOI：10.1016/j.jhep.2022.05.041

抽象的

背景和目的：慢性乙型肝炎病毒 (HBV) 感染影响全球超过 2.5 亿人。目前的抗病毒药物有效抑制病毒复制，但通常需要长期治疗。慢性 HBV 的持续功能性治愈发生在少数接受或不接受抗病毒治疗的个体中，更好地定义介导功能性治愈的因素对于改进免疫治疗策略至关重要。我们旨在比较不同程度病毒控制患者的 HBV 特异性 T 细胞反应。

方法：我们采集了124名HBV感染者的血液，包括急性自限性HBV感染、慢性感染和功能性治愈的慢性感染。我们通过 ELISpot 筛选 HBV 特异性 T 细胞特异性，使用细胞内细胞因子染色评估 HBV 特异性 T 细胞的功能，并使用人白细胞抗原 (HLA) II 类四聚体染色表征 HBV 特异性 CD4 T 细胞，所有直接离体。

结果： ELISpot 筛查很容易识别出急性缓解感染中的 HBV 特异性 CD4 和 CD8 T 细胞反应，而慢性感染中反应更有限。与慢性感染相比，应用更敏感的检测显示功能性 HBV 特异性 CD4 T 细胞的频率更高，但 CD8 T 细胞在功能性治愈中的频率更高。与慢性感染相比，使用 HLA 多聚体的功能独立分析还发现，功能性治愈中更多的 HBV 特异性 CD4 T 细胞反应，在急性和慢性感染后都出现了 CD4 T 细胞记忆。

结论：与慢性 HBV 感染相比，慢性 HBV 感染的功能性治愈与更高频率的功能性 HBV 特异性 CD4 记忆 T 细胞反应相关。数据支持诱导 HBV 功能性治愈的免疫治疗方法也应该旨在改善 CD4 T 细胞反应。

总结：慢性乙型肝炎的免疫治疗方法试图模仿自发控制 HBV 感染的患者的免疫反应，即所谓的功能性治愈。然而，究竟是什么定义了保护性免疫反应仍不清楚。在这里，我们表明功能性治愈与强大的 HBV 特异性 CD4 T 细胞反应相关，这一直很难研究，表明 CD4 免疫应考虑用于 HBV 免疫疗法。

关键词：CD4 T细胞； HLA多聚体；乙型肝炎病毒; T细胞功能；功能性治愈。

版权所有 © 2022。Elsevier B.V. 出版

StephenW

Hepatitis B virus-specific CD4 T-cell responses differentiate functional cure from chronic surface antigen + infection
Ruben C Hoogeveen  1 , Suzan Dijkstra  2 , Lea M Bartsch  2 , Hannah Drescher  2 , Jasneet Aneja  2 , Maxwell P Robidoux  2 , James A Cheney  2 , Jörg Timm  3 , Adam Gehring  4 , Paulo Sergio Fonseca de Sousa  5 , Lya Ximenez  5 , Luis Baiao Peliganga  6 , Anita Pitts  2 , Fiona Evans Blackburn  2 , André Boonstra  7 , Arthur Y Kim  8 , Lia L Lewis-Ximenez  5 , Georg M Lauer  9
Affiliations
Affiliations

    1
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA; Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
    2
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
    3
    Institute of Virology, Heinrich Heine University, University Hospital, Düsseldorf, Germany.
    4
    Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
    5
    Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
    6
    Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil; Faculdade de Medicina da Universidade Agostinho Neto, Luanda, Angola; Ministério da Saúde de Angola, Luanda, Angola.
    7
    Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
    8
    Division of Infectious Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
    9
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, USA. Electronic address: [email protected].

    PMID: 35716846 DOI: 10.1016/j.jhep.2022.05.041

Abstract

Background and aims: Chronic hepatitis B virus (HBV) infection affects over 250 million individuals globally. Current antivirals effectively suppress viral replication, but usually require long-term treatment. Sustained functional cure of chronic HBV occurs in few individuals with or without antiviral treatment and a better definition of what mediates functional cure is essential for improving immunotherapeutic strategies. We aimed to compare HBV-specific T-cell responses in patients with different degrees of viral control.

Methods: We obtained blood from 124 HBV-infected individuals, including acute self-limiting HBV infection, chronic infection, and chronic infection with functional cure. We screened for HBV-specific T-cell specificities by ELISpot, assessed the function of HBV-specific T-cells using intracellular cytokine staining, and characterized HBV-specific CD4 T-cells using human leukocyte antigen (HLA) class II tetramer staining, all directly ex vivo.

Results: ELISpot screening readily identified HBV-specific CD4 and CD8 T-cell responses in acute resolving infection compared with more limited reactivity in chronic infection. Applying more sensitive assays revealed higher frequencies of functional HBV-specific CD4 T-cells, but not CD8 T-cells, in functional cure compared to chronic infection. Function independent analysis using HLA multimers also identified more HBV-specific CD4 T-cell responses in functional cure compared to chronic infection, with emergence of CD4 T-cell memory both after acute and chronic infection.

Conclusions: Functional cure in chronic HBV infection is associated with higher frequencies of functional HBV-specific CD4 memory T-cell responses compared to chronic HBV infection. The data support that immunotherapeutic approaches to induce HBV functional cure should also aim to improve CD4 T-cell responses.

Lay summary: Immunotherapeutic approaches for chronic hepatitis B attempt to emulate the immune response in patients who control HBV infection spontaneously, so called functional cure. However, what exactly defines protective immune responses remains unclear. Here we show that functional cure is associated with robust HBV-specific CD4 T-cell responses, which have been very difficult to study, indicating that CD4 immunity should be considered for HBV immunotherapies.

Keywords: CD4 T-cells; HLA multimer; Hepatitis B virus; T-cell function; functional cure.

Copyright © 2022. Published by Elsevier B.V.