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HIV-1 Vif suppresses antiviral immunity by targeting STING

Cellular & Molecular Immunology volume 19, pages 108–121 (2022)Cite this article

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Abstract

HIV-1 infection-induced cGAS–STING–TBK1–IRF3 signaling activates innate immunity to produce type I interferon (IFN). The HIV-1 nonstructural protein viral infectivity factor (Vif) is essential in HIV-1 replication, as it degrades the host restriction factor APOBEC3G. However, whether and how it regulates the host immune response remains to be determined. In this study, we found that Vif inhibited the production of type I IFN to promote immune evasion. HIV-1 infection induced the activation of the host tyrosine kinase FRK, which subsequently phosphorylated the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Vif and enhanced the interaction between Vif and the cellular tyrosine phosphatase SHP-1 to inhibit type I IFN. Mechanistically, the association of Vif with SHP-1 facilitated SHP-1 recruitment to STING and inhibited the K63-linked ubiquitination of STING at Lys337 by dephosphorylating STING at Tyr162. However, the FRK inhibitor D-65495 counteracted the phosphorylation of Vif to block the immune evasion of HIV-1 and antagonize infection. These findings reveal a previously unknown mechanism through which HIV-1 evades antiviral immunity via the ITIM-containing protein to inhibit the posttranslational modification of STING. These results provide a molecular basis for the development of new therapeutic strategies to treat HIV-1 infection.

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Acknowledgements

This work was supported by grants from the Program of Shanghai Academic Research Leader (21XD1402900), the Natural Science Foundation of Shanghai (21ZR1481400), the National Natural Science Foundation of China (31972900), the National Youth Talent Support Program (Ten Thousand Talent Program), the National Key Research and Development Program of China (2018YFC1705505), and the National Megaproject on Key Infectious Diseases (2017ZX10202102). We thank Dr. Y. Zheng (Michigan State University, Michigan) for HA-Vif, Dr. B. Sun (Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China) for Flag-STING, Dr. D. Sauter (Ulm University, Meyerhofstrasse, Germany) for pBR322-HIV-1-M-NL4-3-IRES-eGFP env STOP plasmid (pseudotyping is required for infection), and Dr. J. Han (Xiamen University, Xiamen, China) for cDNAs encoding SRC-family kinases.

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Author notes

  1. These authors contributed equally: Yu Wang, Gui Qian, Lingyan Zhu, Zhuo Zhao.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Shanghai Institute of Infectious Disease and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200032, China

    Yu Wang, Gui Qian, Lingyan Zhu, Yinan Liu, Yihua Zhang, Xiaoyan Zhang & Dapeng Yan

  2. National Engineering Research Centre of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing, 400038, China

    Yu Wang, Zhuo Zhao, Xiaokai Zhang, Tingrong Xiong, Hao Zeng & Quanming Zou

  3. Department of Basic Courses, NCO School, Army Medical University, Shijiazhuang, 050081, China

    Yu Wang

  4. Biosafety Level 3 Laboratory, Fudan University, Shanghai, 200032, China

    Wendong Han

  5. National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, 130012, China

    Xianghui Yu

  6. Institute of Virology and AIDS Research, The First Hospital of Jilin University, Changchun, 130061, China

    Xiaofang Yu

  7. Shanghai Key Laboratory of Organ Transplantation, Zhongshan Hospital & Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China

    Jianqing Xu

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Contributions

JX, QZ, and DY conceived the project and designed the experiments. YW and DY wrote the manuscript. YW, GQ, LZ, and ZZ performed most of the experiments and analyzed the data. YL, WH, XZ, YZ, and TX assisted with the experiments and provided technical help. HZ, XY, XY, and XZ provided comments and assisted with manuscript preparation.

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Correspondence to Jianqing Xu, Quanming Zou or Dapeng Yan.

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Wang, Y., Qian, G., Zhu, L. et al. HIV-1 Vif suppresses antiviral immunity by targeting STING. Cell Mol Immunol 19, 108–121 (2022). https://doi.org/10.1038/s41423-021-00802-9

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