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Here, we investigated HBV-induced alterations in host gene expression in primary human hepatocytes (PHH) to identify host factors exploited by the virus for replication and persistence. Whole-transcriptome sequencing (WTS) of HBV-infected PHH identified host pathways with potential roles in the HBV life cycle. RNA interference-based functional screening of dysregulated candidate genes identified cyclin L1 (CCNL1) as a key host factor. RNAi-mediated knockdown of CCNL1 reduced HBV gene expression, including hepatitis B surface antigen (HBsAg). Mechanistically, CCNL1 regulates phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) at serine 2 (S2), consistent with a role in transcriptional regulation. CCNL1 knockdown further reduced the binding of total and phospho- (Ser2\/Ser5) RNAPII, pan-acetylated histone H3 (H3ac), and H3K27ac to HBV covalently closed circular DNA (cccDNA), indicating impaired cccDNA-dependent transcription. In addition, CCNL1 expression was elevated in chronic hepatitis B patients compared with those with resolved infection. Collectively, these data demonstrate that CCNL1 promotes HBV transcription and replication through modulation of RNAPII phosphorylation and chromatin-associated transcriptional activity, identifying CCNL1 as a potential host susceptibility factor for HBV. Importance: Hepatitis B virus infection remains a major threat to human health in areas with high prevalence. There is need to fully understand the complex interactions between the virus and human host factors\/processes to support ongoing efforts to develop anti-HBV therapies that can be used with existing therapies to achieve a better cure. HBV relies on host cellular factors and biological processes to establish and maintain efficient infection, making host\u2013virus interactions attractive targets for therapeutic intervention. Thus, identifying host factors that support and\/or restrict HBV infection is essential for understanding the molecular basis of chronic HBV infection and for developing host-targeting anti-HBV drugs. This study identifies cyclin L1 (CCNL1) as a host susceptibility factor that promotes HBV transcription and replication through regulation of RNA polymerase II activity and or post-transcriptional mechanisms.<\/jats:p>","DOI":"10.3390\/v18050545","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:11:13Z","timestamp":1778271073000},"page":"545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Cyclin L1 as a Host Factor Regulating Hepatitis B Virus Replication"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2684-9996","authenticated-orcid":false,"given":"Collins Oduor","family":"Owino","sequence":"first","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"},{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 2, Singapore 117545, Singapore"},{"name":"Department of Biochemistry, Faculty of Science and Technology, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balakrishnan Chakrapani","family":"Narmada","sequence":"additional","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"},{"name":"Experimental Drug Development Centre, Agency for Science, Technology, and Research (A*STAR), 10 Biopolis Way, Chromos, Singapore 138670, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian","family":"Yi Lin","sequence":"additional","affiliation":[{"name":"Experimental Drug Development Centre, Agency for Science, Technology, and Research (A*STAR), 10 Biopolis Way, Chromos, Singapore 138670, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline Poh Kim","family":"Aw","sequence":"additional","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivrithi","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovi Tan","family":"Siying","sequence":"additional","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4879-4586","authenticated-orcid":false,"given":"Marie-Laure","family":"Plissonnier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Lyon 1, Inserm, PaThLiv, U1350, 69003 Lyon, France"},{"name":"Institut Hospitalo-Universitaire (IHU) EVEREST, Lyon Hepatology Institute, 69004 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thangavelu Thangavelu","family":"Matan","sequence":"additional","affiliation":[{"name":"Experimental Drug Development Centre, Agency for Science, Technology, and Research (A*STAR), 10 Biopolis Way, Chromos, Singapore 138670, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niranjan","family":"Shirgaonkar","sequence":"additional","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Bifani","sequence":"additional","affiliation":[{"name":"Infectious Diseases Translational Research Programme, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Blk MD4, Level 2, Singapore 117545, Singapore"},{"name":"A*STAR Infectious Diseases Labs, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, #05-13, Immunos, Singapore 138648, Singapore"},{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4978-0875","authenticated-orcid":false,"given":"Massimo","family":"Levrero","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Lyon 1, Inserm, PaThLiv, U1350, 69003 Lyon, France"},{"name":"Institut Hospitalo-Universitaire (IHU) EVEREST, Lyon Hepatology Institute, 69004 Lyon, France"},{"name":"Department of Hepatology, Hospices Civils de Lyon, 69004 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giridharan","family":"Periyasamy","sequence":"additional","affiliation":[{"name":"Experimental Drug Development Centre, Agency for Science, Technology, and Research (A*STAR), 10 Biopolis Way, Chromos, Singapore 138670, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seng","family":"Gee Lim","sequence":"additional","affiliation":[{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, Level 10, 1E Kent Ridge Road, Singapore 119228, Singapore"},{"name":"Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore"},{"name":"Division of Gastroenterology and Hepatology, National University Hospital, National University Health System, 5 Lower Kent Ridge Road, Singapore 119074, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramanuj","family":"DasGupta","sequence":"additional","affiliation":[{"name":"Laboratory of Precision Medicine and Cancer Evolution, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), 60 Biopolis St., #02-01 Genome, Singapore 138672, Singapore"},{"name":"CRUK Scotland Institute, School of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.jhep.2017.03.021","article-title":"EASL 2017 Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection","volume":"67","author":"Lampertico","year":"2017","journal-title":"J. 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