{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T05:35:33Z","timestamp":1792992933605,"version":"4.5.0"},"reference-count":0,"publisher":"The Korean Association for the Study of the Liver","issue":"4","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/3.0\/"}],"content-domain":{"domain":["e-cmh.org"],"crossmark-restriction":true},"short-container-title":["Clin Mol Hepatol"],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>Background\/Aims: PEGylated interferon-\u03b1 (PEGIFN\u03b1) shows promise in treating chronic hepatitis B (CHB), yet patient response remains suboptimal. While suppressing hepatitis B virus (HBV) antigens by RNA interference (RNAi) could enhance PEGIFN\u03b1 efficacy in CHB patients, the underlying immunological mechanisms remain obscure.Methods: Using our newly established extracellular humanized IFNAR mouse model of chronic HBV infection, we evaluated the efficacy of a GalNac-conjugated siRNA alone or in combination with PEGIFN\u03b1. Phenotypic and functional characteristics of immune cells were assessed by flow cytometry, ELISpot, and single-cell RNA sequencing (scRNA-seq).Results: High circulating HBsAg reduced antiviral effects and immune responsiveness of PEGIFN\u03b1. Combined PEGIFN\u03b1 and RNAi therapy synergistically and durably suppressed HBsAg (~4log&lt;sub&gt;10&lt;\/sub&gt; IU\/mL, vs. PBS) and achieved HBsAg seroconversion in ~30% of mice, outperforming either monotherapy. Mechanistically, PEGIFN\u03b1 enhanced global T and B cell function, whereas combined therapy further amplified HBV-specific T and B cell responses. scRNA-seq analysis indicated that combined therapy attenuated inhibitory B cell-B cell interactions, strengthened MHC-I-mediated T cell crosstalk, and enhanced MHC-II signaling networks across B cells and hepatocytes\/CD8&lt;sup&gt;+&lt;\/sup&gt; T cells, collectively improving the lymphocyte functionality and facilitating HBsAg seroconversion. Reinforcing MHC-I\/II signaling with agonistic antibodies (\u03b14-1BB, \u03b1CD40) or IL-2-Fc further potentiated antiviral immune responses of combinational regimen.Conclusions: Combined RNAi and PEGIFN\u03b1 therapy exerts synergistic antiviral effects by relieving HBV antigen-induced immune tolerance and orchestrating a functional T cell-B cell crosstalk network centered on MHC-I\/II signaling. Enhancing antigen presentation pathways represents a promising adjunctive strategy to improve functional cure rate of CHB.<\/jats:p>","DOI":"10.3350\/cmh.2026.0385","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T07:47:37Z","timestamp":1789112857000},"page":"e2026.0385","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RNA interference-mediated hepatitis B virus antigen shutdown enhances the antiviral immune effects of PEGylated interferon-\u03b1 via T and B cell crosstalk remodeling"],"prefix":"10.3350","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-331X","authenticated-orcid":true,"given":"Wenjing","family":"Zai","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China"},{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China"},{"name":"Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kongying","family":"Hu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Immunity & Inflammation, Department of Pathogen Biology, Naval Medical University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengying","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyang","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China"},{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Gao","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Research Unit of 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(CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9647-0239","authenticated-orcid":true,"given":"Jieliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic 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