Hepatitis B virus-specific CD4 T cell responses differentiate functional cure from chronic surface antigen+ infection

Ruben C. Hoogeveen, Suzan Dijkstra, Lea M. Bartsch, Hannah K. Drescher, Jasneet Aneja, Maxwell P. Robidoux, James A. Cheney, Joerg Timm, Adam Gehring, Paulo Sergio Fonseca de Sousa, Lya Ximenez, Luis Baiao Peliganga, Anita Pitts, Fiona B. Evans, André Boonstra, Arthur Y. Kim, Lia L. Lewis-Ximenez, Georg M. Lauer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Scopus)

Abstract

Background & Aims: With or without antiviral treatment, few individuals achieve sustained functional cure of chronic hepatitis B virus (HBV) infection. 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 those with 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 the emergence of CD4 T cell memory both after acute and chronic infection. Conclusions: Functional cure is associated with higher frequencies of functional HBV-specific CD4 memory T cell responses. Thus, immunotherapeutic approaches designed to induce HBV functional cure should also aim to improve CD4 T cell responses. Lay summary: Immunotherapy is a form of treatment that relies on harnessing the power of an individual's immune system to target a specific disease or pathogen. Such approaches are being developed for patients with chronic HBV infection, in an attempt to mimic the immune response in patients who control HBV infection spontaneously, achieving a so-called functional cure. However, what exactly defines protective immune responses remains unclear. Herein, we show that functional cure is associated with robust responses by HBV-specific CD4 T cells (a type of immune cell).

Original languageEnglish
Pages (from-to)1276-1286
Number of pages11
JournalJournal of Hepatology
Volume77
Issue number5
Early online date15 Jun 2022
DOIs
Publication statusPublished - 1 Nov 2022

Bibliographical note

Funding Information:
The work was funded by grant support from NIH ( R01 AI148648 to G.M.L. and U19 AI082630 to G.M.L. and A.Y.K.), Janssen Pharma (to G.M.L.), NVGE Gastrostart 2019.25 (to R.C.H.), Deutsche Forschungsgemeinschaft ( BA7175/1-1 to L.M.B. and DR1161/1-1 to H.D.).

Publisher Copyright:
© 2022 European Association for the Study of the Liver

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