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

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.

References

  1. Sohn, W. J. et al. Novel transcriptional regulation of the schlafen-2 gene in macrophages in response to TLR-triggered stimulation. Mol. Immunol. 44, 3273–3282 (2007)

    Article  CAS  Google Scholar 

  2. Yoneyama, M. et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175, 2851–2858 (2005)

    Article  CAS  Google Scholar 

  3. Schwarz, D. A., Katayama, C. D. & Hedrick, S. M. Schlafen, a new family of growth regulatory genes that affect thymocyte development. Immunity 9, 657–668 (1998)

    Article  CAS  Google Scholar 

  4. Geserick, P., Kaiser, F., Klemm, U., Kaufmann, S. H. & Zerrahn, J. Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif. Int. Immunol. 16, 1535–1548 (2004)

    Article  CAS  Google Scholar 

  5. Berger, M. et al. An Slfn2 mutation causes lymphoid and myeloid immunodeficiency due to loss of immune cell quiescence. Nature Immunol. 11, 335–343 (2010)

    Article  CAS  Google Scholar 

  6. Fritz, C. C. & Green, M. R. HIV Rev uses a conserved cellular protein export pathway for the nucleocytoplasmic transport of viral RNAs. Curr. Biol. 6, 848–854 (1996)

    Article  CAS  Google Scholar 

  7. Fischer, U., Huber, J., Boelens, W. C., Mattaj, I. W. & Luehrmann, R. The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs. Cell 82, 475–483 (1995)

    Article  CAS  Google Scholar 

  8. Malim, M. H., Hauber, J., Le, S. Y., Maizel, J. V. & Cullen, B. R. The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature 338, 254–257 (1989)

    Article  CAS  ADS  Google Scholar 

  9. Van Damme, N. et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 3, 245–252 (2008)

    Article  CAS  Google Scholar 

  10. Neil, S. J., Zang, T. & Bieniasz, P. D. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425–430 (2008)

    Article  CAS  ADS  Google Scholar 

  11. Ganser-Pornillos, B. K., Yeager, M. & Sundquist, W. I. The structural biology of HIV assembly. Curr. Opin. Struct. Biol. 18, 203–217 (2008)

    Article  CAS  Google Scholar 

  12. Coleman, J. R. et al. Virus attenuation by genome-scale changes in codon pair bias. Science 320, 1784–1787 (2008)

    Article  CAS  ADS  Google Scholar 

  13. Zhou, T., Gu, W., Ma, J., Sun, X. & Lu, Z. Analysis of synonymous codon usage in H5N1 virus and other influenza A viruses. Biosystems 81, 77–86 (2005)

    Article  CAS  Google Scholar 

  14. Meintjes, P. L. & Rodrigo, A. G. Evolution of relative synonymous codon usage in human immunodeficiency virus type-1. J. Bioinform. Comput. Biol. 3, 157–168 (2005)

    Article  CAS  Google Scholar 

  15. Frelin, L. et al. Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene. Gene Ther. 11, 522–533 (2004)

    Article  CAS  Google Scholar 

  16. Forsberg, R. & Christiansen, F. B. A codon-based model of host-specific selection in parasites, with an application to the influenza A virus. Mol. Biol. Evol. 20, 1252–1259 (2003)

    Article  CAS  Google Scholar 

  17. Plotkin, J. B. & Dushoff, J. Codon bias and frequency-dependent selection on the hemagglutinin epitopes of influenza A virus. Proc. Natl Acad. Sci. USA 100, 7152–7157 (2003)

    Article  CAS  ADS  Google Scholar 

  18. Grantham, P. & Perrin, P. AIDS virus and HTLV-I differ in codon choices. Nature 319, 727–728 (1986)

    Article  CAS  ADS  Google Scholar 

  19. Wong, E. H. M., Smith, D. K., Rabadan, R., Peiris, M. & Poon, L. L. M. Codon usage bias and the evolution of influenza A viruses. Codon usage biases of influenza virus. BMC Evol. Biol. 10, 253 (2010)

    Article  Google Scholar 

  20. van Weringh, A. et al. HIV-1 modulates the tRNA pool to improve translation efficiency. Mol. Biol. Evol. 28, 1827–1834 (2011)

    Article  CAS  Google Scholar 

  21. Kofman, A. et al. HIV-1 gag expression is quantitatively dependent on the ratio of native and optimized codons. Tsitologiia 45, 86–93 (2003)

    CAS  PubMed  Google Scholar 

  22. Haas, J., Park, E. C. & Seed, B. Codon usage limitation in the expression of HIV-1 envelope glycoprotein. Curr. Biol. 6, 315–324 (1996)

    Article  CAS  Google Scholar 

  23. Berkhout, B. & van Hemert, F. J. The unusual nucleotide content of the HIV RNA genome results in a biased amino acid composition of HIV proteins. Nucleic Acids Res. 22, 1705–1711 (1994)

    Article  CAS  Google Scholar 

  24. Kypr, J. & Mrazek, J. Unusual codon usage of HIV. Nature 327, 20 (1987)

    Article  CAS  ADS  Google Scholar 

  25. Pavon-Eternod, M. et al. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 37, 7268–7280 (2009)

    Article  CAS  Google Scholar 

  26. Dittmar, K. A., Mobley, E. M., Radek, A. J. & Pan, T. Exploring the regulation of tRNA distribution on the genomic scale. J. Mol. Biol. 337, 31–47 (2004)

    Article  CAS  Google Scholar 

  27. Coccia, E. M., Krust, B. & Hovanessian, A. G. Specific inhibition of viral protein synthesis in HIV-infected cells in response to interferon treatment. J. Biol. Chem. 269, 23087–23094 (1994)

    CAS  PubMed  Google Scholar 

  28. Connor, R. I., Chen, B. K., Choe, S. & Landau, N. R. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology 206, 935–944 (1995)

    Article  CAS  Google Scholar 

Download references

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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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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The authors declare no competing financial interests.

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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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