The HBV basal core promoter mutation confers a replicative advantage and transcriptionally reprograms hepatocytes toward HCC subtypes
Year: 2026
Type: preprint
Abstract: Background: Hepatitis B virus (HBV) basal core promoter (BCP) and precore (PC) mutations occur during chronic HBV infection with the BCP-mutant being associated with increased hepatocellular carcinoma (HCC) risk. Objectives: The effects of these mutants on viral replication, hepatocyte biology, and carcinogenesis remain poorly defined. To address this, we characterized BCP- and PC-mutants using human hepatocyte chimeric mice and asked whether the resulting infection-induced transcriptomes correspond to subsets of human HBV-related hepatocellular carcinomas (HBV-HCCs). Design: Isogenic wild-type (WT), BCP- and PC-mutants of HBV genotypes A, C, and D (HBV-A, -C, -D) were generated from recombinant covalently-closed circular DNA to infect chimeric mice. HBV-HCC transcriptomic datasets from The Cancer Genome Atlas (TCGA) were used to stratify association of HBV variants with HCC subtypes. Results: WT, BCP-mutant, and PC-mutant HBV sequences remained genetically stable. The BCP mutation, but not the PC mutation, accelerated the rise in serum viremia in HBV-D- and HBV-A-infected chimeras; in HBV-C, acceleration required both (PC+BCP) mutations. Further comparisons of HBV-D variants revealed that the BCP-mutant increased intrahepatic viral DNA, viral protein expression, and upregulated cancer-related pathways, including transcripts associated with a subset of HBV-HCCs. Analysis of HBV-HCC samples from the TCGA revealed that tumors often harbor a mixture of WT and mutant transcripts, and that WT- and BCP-mutant-associated HCCs exhibit distinct transcriptional profiles. Conclusions: The HBV BCP-mutant directly perturbs hepatocyte homeostasis via virus-intrinsic mechanisms, selectively activating cancer-related pathways and defining a molecularly distinct subset of HBV-HCC. These findings suggest that HBV variants form distinct subcategories of HBV-HCCs.
Authors: Leon L. Seifert, Georgios Dangas, Hoyin Chu, Yingpu Yu, Kosuke Ogata, Xupeng Hong, Mengyin Zhang, Yichen Zhou, Chenhui Zou, Alireza Ramandi, Corrine Quirk, Evgenia Moschogianni, Catherine A. Freije, Antonis Athanasiadis, Leonardo Gonzales, Luis Chiriboga, Clifton Fulmer, Hong Hur, Manoj Kandpal, Anna S. Lok, Caleb Lareau, William M. Schneider, Charles M. Rice, Eleftherios Michailidis, Ype P. de Jong
Language: English
Topic: Hepatitis B Virus Studies
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Damon Runyon Cancer Research Foundation, Robertson Foundation, Georgia Clinical and Translational Science Alliance, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Stavros Niarchos Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, National Center for Complementary and Integrative Health
Awards: G112449207, Virus-host interactions for a cure against HBV, G6603456033, A proteomics atlas of HIV/HBV infections for curing HBV, Impact of HIV co-infections and comorbidities on circadian rhythm in the liver, The Human DNA virome: from petabase scale to single-cell resolution, Launching HBV with RNA to assess antiviral resistance and explore fundamental aspects of virus-host biology, Breaching the species barrier: Towards an immunocompetent HBV-susceptible mouse model, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success, Enhancing immune regulation in gene therapy for hemophilia, G912998538
OpenAlex ID: W7214078866