- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30437
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
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. |
|