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The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1

Nature Immunology volume 11, pages 1005–1013 (2010)Cite this article

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Abstract

Viral infection triggers innate immune sensors to produce type I interferon. However, infection of T cells and macrophages with human immunodeficiency virus (HIV) does not trip those alarms. How HIV avoids activating nucleic acid sensors is unknown. Here we found that the cytosolic exonuclease TREX1 suppressed interferon triggered by HIV. In Trex1−/− mouse cells and human CD4+ T cells and macrophages in which TREX1 was inhibited by RNA-mediated interference, cytosolic HIV DNA accumulated and HIV infection induced type I interferon that inhibited HIV replication and spreading. TREX1 bound to cytosolic HIV DNA and digested excess HIV DNA that would otherwise activate interferon expression via a pathway dependent on the kinase TBK1, the adaptor STING and the transcription factor IRF3. HIV-stimulated interferon production in cells deficient in TREX1 did not involve known nucleic acid sensors.

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Figure 1: TREX1 deficiency inhibits HIV replication and activates IFN-β in response to HIV infection.
Figure 2: HIV-stimulated expression of interferon is IRF3 dependent.
Figure 3: Cytosolic HIV DNA in Trex1−/− cells is the trigger for interferon expression.
Figure 4: Recognition of HIV products of reverse transcription by enzymatically active TREX1 suppresses interferon induction.
Figure 5: TREX1-specific siRNA treatment induces IFN-α and IFN-β and inhibits HIV replication in primary human immune cells.
Figure 6: HIV-stimulated interferon induction requires IRF3, TBK1 and STING.

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Acknowledgements

We thank D. Stetson (University of Washington) for wild-type, Trex1−/− and Trex1−/−Irf3−/− primary MEFs, under agreement with D. Barnes and T. Lindahl (Cancer Research UK); J. Jung (University of Southern California) for RIG-I-deficient (Ddx58−/−) MEFs; S. Harvey and F. Perrino (Wake Forest University) for wild-type and Trex1−/− transformed MEFs; A. Engelman (Dana-Farber Cancer Institute) for the HIV-luciferase plasmid (pNL4-3/Env−); D. Gabuzda (Dana-Farber Cancer Institute) for the HIV-GFP plasmid (pNL4-3/Env−); T. Fujita (Kyoto University) for antiserum to mouse IRF3; S. Nagata (Kyoto University) for the hemagglutinin-tagged MAVS plasmid; K. Fitzgerald (University of Massachusetts) for siRNA and inhibitors of RNA polymerase III; J. Hiscott (McGill University) for IFNB-luciferase plasmid; L. Gehrke (Harvard Medical School) for CMV–renilla luciferase plasmid; and members of the Lieberman lab for discussions. Supported by the US National Institutes of Health (AI45587 to J.L., and T32 HL066987 to N.Y.), the Harvard Center for AIDS Research (N.Y.), Harvard Summer Honors Undergraduate Research Program (A.D.R.-M.) and Deutsche Forschungsgemeinschaft (Le 1074/3-1 to M.A.L.-K.).

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  1. and Department of Pediatrics, Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital, Boston, Harvard Medical School, Boston, Massachusetts, USA

    Nan Yan, Ashton D Regalado-Magdos, Bart Stiggelbout & Judy Lieberman

  2. Children's Hospital, Technical University Dresden, Dresden, Germany

    Min Ae Lee-Kirsch

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  1. Nan Yan
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N.Y. conceived of the study, designed and did most experiments and helped write the paper; A.D.R.-M. and B.S. helped do the experiments; M.A.L.-K. provided human cell lines and scientific advice; and J.L. conceived of and supervised the study and helped write the paper.

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Correspondence to Judy Lieberman.

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Yan, N., Regalado-Magdos, A., Stiggelbout, B. et al. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 11, 1005–1013 (2010). https://doi.org/10.1038/ni.1941

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