ZFP36L2 is an interferon β -induced inhibitor that restricts the nuclear export of HIV-1 transcripts.

Type I interferons restrict HIV-1 replication by inducing antiviral genes, but the full spectrum of their effectors remains incompletely defined. Here we identify ZFP36L2, a nuclear RNA-binding protein, as an IFN-β-induced inhibitor of HIV-1 infection. Silencing of ZFP36L2 impairs IFN-β-mediated HIV-1 inhibition, whereas overexpression of ZFP36L2 suppresses viral replication. Notably, reconstitution of ZFP36L2 in CD4⁺ T cells from HIV-1-infected individuals reduces viral spread ex vivo, and ZFP36L2 transcript levels inversely correlate with plasma viral loads in vivo. Mechanistically, ZFP36L2 binds to the HIV-1 Rev protein and inhibits the nuclear export of Rev response element-containing viral transcripts, thereby blocking downstream viral protein expression. A Rev mutant lacking amino acids 109-116 fails to bind ZFP36L2 and exhibits resistance to ZFP36L2-mediated inhibition, underscoring the functional significance of this interaction. These findings establish ZFP36L2 as an IFN-β-induced antiviral factor that suppresses HIV-1 replication through Rev-dependent inhibition of viral RNA export.