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HTLV-1 early or infectious replication depends on Tax; during HTLV-1 late infection, HBZ plays a crucial role in driving the proliferation of infected cells and maintaining viral persistence. The biphasic replication pattern of HTLV-1 dictated by Tax and HBZ represents a result of viral host adaptation, but how HTLV-1 coordinates Tax and HBZ expression to facilitate early and late infection remains elusive. Here we reveal that HBZ RNA splicing exhibits distinct patterns in Tax+ and Tax- HTLV-1 infected cells. We demonstrate that Tax interacts with the host spliceosome and inhibits HBZ splicing by competitively binding splicing factors including WDR83 and GPATCH1. As a result, Tax confers a natural constraint on HBZ, counterbalancing its anti-replication effect at HTLV-1 early infection, while unleashing HBZ to drive HTLV-1 mitotic propagation during late infection. The splicing-dependent restriction of HBZ by Tax thus represents a critical interplay central to HTLV-1 persistence.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013381","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T17:57:10Z","timestamp":1753725430000},"page":"e1013381","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Splicing-dependent restriction of the HBZ gene by Tax underlies biphasic HTLV-1 infection"],"prefix":"10.1371","volume":"21","author":[{"given":"Yi","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuwen","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxin","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benquan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sikai","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijia","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoning","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorui","family":"Zuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Matsuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2003-7201","authenticated-orcid":true,"given":"Guangyong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"issue":"12","key":"ppat.1013381.ref001","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3390\/jcm6120111","article-title":"Viral 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