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The tegument proteins, which are characteristic of herpesviruses, play a crucial role in the envelopment of virions and evasion of host immune defenses, such as the interferon \u03b2 (IFN\u03b2) signaling pathway. However, the precise mechanisms through which the HHV-6B tegument proteins modulate the IFN\u03b2 pathway are not yet fully understood. In this study, we identified a novel function of the HHV-6B tegument protein U65 as an inhibitor of IFN\u03b2 production. Additionally, two host histone proteins, hCG_2039566 (H2ACG) and H2AC7, were identified as positive regulators of innate immune pathways. U65 interacts with H2ACG and H2AC7, impairing their ability to promote the IFN\u03b2 pathway. Furthermore, we demonstrated that U65 plays critical roles during HHV-6B infection. This study highlights a critical strategy employed by HHV-6B to evade immune defenses, shedding light on its mechanisms for counteracting host responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>HHV-6B is a virus that primarily infects T cells and can cause illnesses like exanthem subitum and is linked to neurological conditions such as multiple sclerosis. Like other herpesviruses, HHV-6B likely has special proteins that help it avoid the body\u2019s immune defenses, such as the IFN\u03b2 signaling pathway, which plays a key role in fighting viral infections. However, how these viral proteins interfere with the immune response is not yet fully understood. In this study, we discovered that one of the HHV-6B proteins, U65, blocks the production of IFN\u03b2, weakening the antiviral defenses. We also found that two human proteins, hCG_2039566 and H2AC7, promote the immune system, but U65 prevents them from doing so. This study reveals a new way that HHV-6B escapes the immune system, providing insight into how the virus efficiently establishes infections and how we might target its ability to evade immunity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00984-25","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T13:00:16Z","timestamp":1757941216000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Human herpesvirus 6B U65 binds to histone proteins and suppresses interferon production"],"prefix":"10.1128","volume":"99","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7532-1587","authenticated-orcid":false,"given":"Haokun","family":"Li","sequence":"first","affiliation":[{"name":"Department of Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences","place":["Okayama, 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