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Although HBV-infected patients benefit\n                        from drug regimens that help control chronic infection, they are rarely\n                        clinically cured of HBV. The HBV genome persists in the nucleus of infected\n                        hepatocytes as a covalently closed circular DNA (cccDNA) molecule, a\n                        reservoir of HBV DNA molecules that serves as the template for reactivation\n                        of long-term chronic HBV. Despite playing a central role in the viral life\n                        cycle, little is understood about where cccDNA molecules localize, why they\n                        are so stable, and how they impact the host nuclear compartment. Here, we\n                        show that HBV genomes in cell line models provoke cellular replication\n                        stress early in infection, which culminates in global DNA damage response\n                        (DDR) signals. HBV-induced replication stress early in infection correlates\n                        with the onset of virus replication and expression of viral genes, forming\n                        viral genome reservoirs in distinct subnuclear compartments. Using a novel\n                        high-throughput chromosome conformation capture technology that monitors the\n                        localization of HBV cccDNA molecules in few cells, we show that cccDNA\n                        molecules persist in the vicinity of transcriptionally active cellular\n                        promoters. Most of these sites contain binding elements for the\n                        stress-response protein DDIT3 (DNA damage inducible transcript 3).\n                        RNAi-mediated knockdown of DDIT3 rescues HBV-induced replication stress\n                        without altering the cccDNA reservoir. Our findings contribute to the\n                        understanding of how HBV\u2019s navigation of the host nuclear environment\n                        regulates genome stability, identifying functional targets for development\n                        of therapies against HBV-induced liver cancer.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Hepatitis B virus (HBV) is the leading infectious cause of liver cancer\n                            globally. The virus persists in the nucleus long term by forming\n                            reservoirs in human liver cells. We have discovered that HBV DNA\n                            localizes to sites on the host genome associated with transcriptionally\n                            active chromatin, and in doing so, HBV interferes with the host\u2019s\n                            ability to efficiently undergo amplification. This results in the\n                            induction of cellular DNA breaks, which we propose contributes to\n                            eventual cancer progression. Our findings provide new insights into how\n                            HBV infection may lead to liver cancer.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01014-25","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T12:53:21Z","timestamp":1760100801000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Association of hepatitis B virus genomes with active chromatin hubs                    challenges host replication fidelity, leading to DNA damage"],"prefix":"10.1128","volume":"99","author":[{"given":"Gavin J.","family":"Marcoe","sequence":"first","affiliation":[{"name":"Cancer Biology Graduate Program","place":["Madison, USA"]},{"id":[{"id":"https:\/\/ror.org\/01y2jtd41","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute for Molecular Virology","place":["Madison, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clairine I. 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