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Yang, S.* ; Nebioglu, F.* ; Pham, M.T.* ; Lin, Y.* ; Pichlmair, A. ; Nkongolo, S.* ; Scaturro, P.* ; Urban, S.* ; Seitz, S.* ; Bartenschlager, R.*

Hepatitis B virus proteome analysis identifies apolipoprotein C1 facilitating particle production and virus entry.

Hepatology, DOI: 10.1097/hep.0000000000001864 (2026)
Postprint DOI PMC
Open Access Green
BACKGROUND AIMS: Antiviral therapies targeting hepatitis B virus (HBV) suppress viral replication, but rarely achieve functional cure. Understanding HBV-host cell interaction is crucial for developing novel therapeutic approaches. Here, we report host cell proteins associated with HBV virions and filamentous subviral particles (fSVPs) and characterize one host cell protein, apolipoprotein C1 (ApoC1), mechanistically. METHODS: Highly purified HBV virions and fSVPs were obtained by sequential use of several biophysical methods. Particles were analyzed by mass spectrometry and associated proteins were evaluated phenotypically using an HBV infection model. The top hit, ApoC1 was characterized in detail. RESULTS: Alongside the established HBV-associated chaperones HSP90AB1 and HSC70, we identified several apolipoprotein-related factors associated with virions and fSVPs. RNAi-based phenotypic validation identified strongest effects for ApoC1, likely due to two complementary effects. First, ApoC1 depletion reduced intracellular cholesterol level impairing HBV infection and SVP production, which was compensated by exogenous cholesterol addition. Second, ApoC1 that is mainly enriched in high-density lipoprotein (HDL), associates with HBV virions and fSVPs and increases HBV infectivity. The same was found for hepatitis D virus (HDV), a satellite virus utilizing HBV envelopes. Supplementation of exogenous HDL enhanced infection via scavenger receptor class B type 1 (SR-B1), the natural HDL receptor. Consistently, inhibition of SR-B1 suppressed HBV and HDV infection. CONCLUSIONS: We established a method for obtaining highly purified HBV virions and fSVPs and identified the HDL component ApoC1 to associate with both particle types. ApoC1 promotes HBV and HDV infection most likely via SR-B1 and facilitates viral entry.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hepatitis B Virus ; Virus ; Apolipoprotein B ; Proteome ; Scavenger Receptor ; Viral Entry ; Hepatitis D Virus ; Hepatitis B; Receptor Sr-bi; Surface-antigen; Reverse-transcriptase; Membrane-fusion; X Protein; Hdl; Binding; Association; Cholesterol; Inhibitors
ISSN (print) / ISBN 0270-9139
e-ISSN 1527-3350
Journal Hepatology
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Grants Center for Immunology of Viral Infections (CiViA) - Danish National Research Foundation
DZIF, TTU Hepatitis
Free and Hanseatic City of Hamburg
German Ministry of Research (DFG)
German Research Center for Infection (DZIF)
DFG
Project "Prevention of Pan-demic-infection-associated Pathology Munich-P3M" (BayVFP 2024-2027)
Deutsche Forschungsgemeinschaft (DFG)