Abstract
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.
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Data supporting the findings of this study are available within the article and its Supplementary Information files. Source data are provided in this paper. Source data are provided with this paper.
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Acknowledgements
We thank all our laboratory members for their contributions to this study. We would also like to thank Shengjia Li and Yuan Liu for their technical support. This study was supported by the National Science Fund for Distinguished Young Scholars (grant no. 82325034), the National Science Fund for Young Scholars (grant no. 82202599; 82202506), Key Program of the National Natural Science Foundation of China (grant No. 82130069), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2023-PT320-01), and the Department of Science and Technology of Liaoning Province Project for the High-Quality Scientific and Technological Development of China Medical University (2023JH2-2020001).
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G.L. directed and conceived the research. H.P., H.C., X.Y. and Z.Y. performed the experiments and analyzed the data. H.S. provided intellectual advice on experimental design. G.L. wrote the manuscript.
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Pang, H., Cui, H., Yin, X. et al. ZFP36L2 is an interferon β -induced inhibitor that restricts the nuclear export of HIV-1 transcripts. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71474-0
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DOI: https://doi.org/10.1038/s41467-026-71474-0
