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However, the modulation of Nef on proviral DNA transcription of latently infected viruses is not well understood. In this study, we found that Nef activated HIV-1 proviral DNA transcription by recruiting Src Family Kinases (SFKs) member Src to stimulate the downstream PI3K\/AKT\/mTOCR1\/CDK9 cellular pathway, and that Naf1 (Nef-associated factor 1), a host protein that is known to suppress HIV-1 transcription, was required for this function of Nef. This seemingly contradictory interplay between Nef and Naf1 was investigated. Naf1 was a repressor of the PI3K\/AKT\/mTOCR1\/CDK9 cellular pathway, but in the presence of Nef, Naf1 was phosphorylated at the Tyrosine-552 by Nef-recruited Src, consequently converting its normal restrictive role to coordinate with Nef to activate proviral DNA transcription. These findings reveal a mechanism by which Nef activates HIV-1 proviral DNA transcription and discover the dual function of Naf1 protein in regulating HIV infection, depending on its phosphorylation status. This study reports a new interaction mode between host factors and viral proteins in regulating HIV-1 replication.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>HIV-1 accessory protein Nef is a multifunctional pathogenic factor; however, the modulation of Nef on proviral DNA transcription of latently infected virus is not well understood. This study demonstrates Nef's role in activating HIV-1 proviral DNA transcription and uncovers the underlying cellular mechanism. Nef recruits Src kinase to phosphorylate Naf1, and the phosphorylation of Naf1 converts its normal restrictive role to coordinate with Nef to activate proviral DNA transcription by stimulating the downstream PI3K\/AKT\/mTOCR1\/CDK9 cellular pathway. These findings also report a new interaction mode between host factors and viral proteins in regulating HIV-1 replication.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00280-25","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T13:00:24Z","timestamp":1745499624000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["HIV-1 Nef activates proviral DNA transcription by recruiting Src kinase to phosphorylate host protein Nef-associated factor 1 to compromise its viral restrictive function"],"prefix":"10.1128","volume":"99","author":[{"given":"Tian-Jiao","family":"Fan","sequence":"first","affiliation":[{"name":"Pingyuan Laboratory, State Key Laboratory of Antiviral Drugs, Henan Normal University","place":["Xinxiang, China"]},{"name":"Shanghai Sci-Tech Inno Center for Infection & Immunity","place":["Shanghai, 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