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Significance TIM proteins inhibit release of HIV-1 and other enveloped viruses. However, it is currently unknown whether and how the virus counteracts this restriction. In this work, we demonstrate that Nef proteins of HIV-1 and other lentiviruses function as antagonists to overcome the TIM-mediated restriction. TIM-1 is more potent at inhibiting release of Nef-deficient HIV-1 relative to wild-type (WT) HIV-1, and ectopic expression of Nef relieves this restriction. Interestingly, we find that SERINC proteins potentiate TIM-mediated inhibition of HIV-1 release likely by stabilizing TIM-1 expression. Our work reveals a role for lentiviralNef in antagonizing TIMs, in part through SERINCs.

TIM-mediated inhibition of HIV-1 release is antagonized by Nef but potentiated by SERINC proteins