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

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.