JHEP reports : innovation in hepatology · 2026
Spatial-quantitative profiling of intrahepatic HBsAg heterogeneity and clustered distribution in chronic HBV infection.
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Xu Mingzhu, Zheng Ye, Wu Min, Qian Yuyan, Lu Wei, Zhang Pingzhao, Liu Jiangxia, Li Fahong, Song Shu, Zhang Jiming, Zhang Xiaonan, Zhang Zhanqing, Chen Jieliang, Yuan Zhenghong
Аннотация
BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg), a hallmark of chronic hepatitis B virus (CHB) infection, is expressed from both covalently closed circular DNA (cccDNA) and integrated HBV DNA. HBsAg exhibits diffuse, scattered, or clustered intrahepatic patterns, yet their variation across disease phases and the relationship to HBV DNA remain unclear.
METHODS: Formalin-fixed paraffin-embedded sections from 385 treatment-naive patients with CHB were analyzed. The immunofluorescence and enhanced in situ hybridization (IF-ISH) assay was coupled with a whole-slide imaging-based quantitative pipeline to delineate the spatial patterns of HBsAg in the context of viral DNA. Laser capture microdissection isolated HBsAg-positive hepatocytes, followed by HBV-enriched Nanopore sequencing and SMART-seq2 based RNA sequencing.
RESULTS: HBeAg-negative individuals showed more clustered HBsAg-positive hepatocytes than HBeAg-positive individuals (55.1% vs. 34.5%). IF-ISH analysis with enhanced sensitivity for HBV DNA confirmed the general mutually exclusive pattern between HBsAg-rich and HBV DNA-positive hepatocytes, while also revealing a subset of colocalization events, together with phase-specific variations in the subcellular (nuclear vs. cytoplasmic) localization of viral DNA. Clustered HBsAg-rich hepatocytes predominantly exhibited cytoplasmic HBV DNA in patients who were HBeAg-positive (54.4%), whereas nuclear HBV DNA was dominant in patients who were HBeAg-negative (78.8%), harboring transcripts derived from integrant and/or cccDNA.
CONCLUSIONS: This study provides quantitative evidence that clustered HBsAg-rich hepatocytes are more prevalent in individuals who are HBeAg-negative and predominantly harbor nuclear-localized HBV DNA originating from integration and/or cccDNA, thereby providing new insights into phase-specific intrahepatic viral heterogeneity and advancing understanding of host-virus interactions in HBV persistence.
IMPACT AND IMPLICATIONS: This study reveals that clustered HBsAg-positive hepatocytes, enriched in individuals who are HBeAg-negative, predominantly contain nuclear HBV DNA originating from integration and/or cccDNA. The mutually exclusive spatial patterns of HBsAg-rich and HBV DNA-positive hepatocytes reflect distinct viral reservoirs and dynamic changes across different phases of chronic HBV infection. These findings provide new insights into the intrahepatic landscape of HBV persistence and may inform phase-specific strategies for functional cure of chronic hepatitis B.
METHODS: Formalin-fixed paraffin-embedded sections from 385 treatment-naive patients with CHB were analyzed. The immunofluorescence and enhanced in situ hybridization (IF-ISH) assay was coupled with a whole-slide imaging-based quantitative pipeline to delineate the spatial patterns of HBsAg in the context of viral DNA. Laser capture microdissection isolated HBsAg-positive hepatocytes, followed by HBV-enriched Nanopore sequencing and SMART-seq2 based RNA sequencing.
RESULTS: HBeAg-negative individuals showed more clustered HBsAg-positive hepatocytes than HBeAg-positive individuals (55.1% vs. 34.5%). IF-ISH analysis with enhanced sensitivity for HBV DNA confirmed the general mutually exclusive pattern between HBsAg-rich and HBV DNA-positive hepatocytes, while also revealing a subset of colocalization events, together with phase-specific variations in the subcellular (nuclear vs. cytoplasmic) localization of viral DNA. Clustered HBsAg-rich hepatocytes predominantly exhibited cytoplasmic HBV DNA in patients who were HBeAg-positive (54.4%), whereas nuclear HBV DNA was dominant in patients who were HBeAg-negative (78.8%), harboring transcripts derived from integrant and/or cccDNA.
CONCLUSIONS: This study provides quantitative evidence that clustered HBsAg-rich hepatocytes are more prevalent in individuals who are HBeAg-negative and predominantly harbor nuclear-localized HBV DNA originating from integration and/or cccDNA, thereby providing new insights into phase-specific intrahepatic viral heterogeneity and advancing understanding of host-virus interactions in HBV persistence.
IMPACT AND IMPLICATIONS: This study reveals that clustered HBsAg-positive hepatocytes, enriched in individuals who are HBeAg-negative, predominantly contain nuclear HBV DNA originating from integration and/or cccDNA. The mutually exclusive spatial patterns of HBsAg-rich and HBV DNA-positive hepatocytes reflect distinct viral reservoirs and dynamic changes across different phases of chronic HBV infection. These findings provide new insights into the intrahepatic landscape of HBV persistence and may inform phase-specific strategies for functional cure of chronic hepatitis B.