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Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11

Nature volume 491, pages 125–128 (2012)Cite this article

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Abstract

In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway1. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.

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Figure 1: SLFN11 inhibits retrovirus production without affecting intracellular vRNA levels.
Figure 2: SLFN11 selectively inhibits viral protein expression on the basis of codon usage.
Figure 3: SLFN11 binds tRNAs and selectively inhibits protein expression based on codon usage.
Figure 4: SLFN11 inhibits replication of wild-type HIV-1 LAI in CEM cells.

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Acknowledgements

We thank D. Smith for help with the HIV replication studies; M. Wood for performing the electron microscope analysis; D. Xu and D.-Y. Song for technical assistance; and J. Young, J. Guatelli, D. Smith, M. Kaul and S. Chanda for discussion. This work was supported in part by NIH AI81019 and AI074967 to M.D.W., NIH P01AI090935, R01GM101982 and R21AI088490 to M.D., and by resources from the UCSD Center for AIDS Research, NIH P30AI36214, and the HINT Program, NIH P01AI090935. The authors declare no competing financial interests.

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Authors and Affiliations

  1. Division of Biological Sciences, Section of Molecular Biology, University of California San Diego, La Jolla, 92093, California, USA

    Manqing Li, Elaine Kao, Xia Gao, Hilary Sandig, Kirsten Limmer & Michael David

  2. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, 60637, Illinois, USA

    Mariana Pavon-Eternod, Thomas E. Jones & Tao Pan

  3. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, 92037, California, USA

    Sebastien Landry & Matthew D. Weitzman

  4. Moores Cancer Center, University of California San Diego, La Jolla, 92093, California, USA

    Michael David

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Contributions

M.L., M.D.W., T.P. and M.D. planned the experiments; M.L., E.K., X.G., M.P.-E., K.L., H.S., T.E.J. and S.L. conducted the experiments; M.L., T.P., M.D.W. and M.D. analysed the data; and M.L. and M.D. wrote the manuscript.

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Correspondence to Michael David.

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Li, M., Kao, E., Gao, X. et al. Codon-usage-based inhibition of HIV protein synthesis by human schlafen 11. Nature 491, 125–128 (2012). https://doi.org/10.1038/nature11433

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