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The \u201cblock-and-lock\u201d strategy aims to enforce durable transcriptional silencing of proviruses, thereby preventing viral rebound upon interruption of antiretroviral therapy. However, the molecular mechanisms governing stable latency remain incompletely understood. Here, we identify protein kinase C (PKC)-dependent phosphorylation of STAT1 and STAT3 at serine 727 as a previously unrecognized regulatory checkpoint controlling HIV-1 transcriptional reactivation. Pharmacological inhibition of this axis using sorafenib, a clinically approved multi-kinase inhibitor, robustly suppresses HIV-1 reactivation across multiple latency models and promotes the establishment of latency in primary CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. Mechanistically, sorafenib attenuates phorbol 12-myristate 13-acetate (PMA)-induced activation of the JAK-STAT and PI3K-Akt signaling pathways, and selectively blocks PKC-mediated phosphorylation of STAT1\/3 at serine 727 without affecting canonical tyrosine phosphorylation (Y701\/Y705). This selective inhibition disrupts transcriptional activation at the HIV-1 long terminal repeat (\n                      <jats:italic toggle=\"yes\">LTR<\/jats:italic>\n                      ), thereby preventing viral reactivation. Importantly, sorafenib does not induce detectable cytotoxicity or alter activation and exhaustion markers in primary CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells, supporting a favorable safety profile\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . Collectively, our findings define a critical role for STAT1\/3 Ser727 in the regulation of HIV-1 latency and establish sorafenib as a promising latency-promoting agent for future applications in the development of a functional cure for HIV-1.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00540-26","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:27:22Z","timestamp":1785763642000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Sorafenib enforces HIV-1 latency by selectively inhibiting PKC-driven STAT1\/3 serine 727 phosphorylation"],"prefix":"10.1128","volume":"70","author":[{"given":"Peipei","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tm3k558","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyue","family":"Meng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Microbiology, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiasheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Engineering Technology Research Center for Combined Vaccines","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixin","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Microbiology, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Microbiology, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-4416","authenticated-orcid":false,"given":"Zhiliang","family":"Gao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tm3k558","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6839-7705","authenticated-orcid":false,"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tm3k558","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8356-030X","authenticated-orcid":true,"given":"Jinfeng","family":"Cai","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/0064kty71","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Microbiology, Zhongshan School of Medicine of Sun Yat-sen University","place":["Guangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"UNAIDS. 2024. 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