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Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection

Nature volume 502, pages 559–562 (2013)Cite this article

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Abstract

Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type 1 (HIV-1), these include widely expressed restriction factors1, such as APOBEC3 proteins2, TRIM5-α3, BST2 (refs 4, 5) and SAMHD1 (refs 6, 7), as well as additional factors that are stimulated by type 1 interferon (IFN)8,9,10,11,12,13,14. Here we use both ectopic expression and gene-silencing experiments to define the human dynamin-like, IFN-induced myxovirus resistance 2 (MX2, also known as MXB) protein as a potent inhibitor of HIV-1 infection and as a key effector of IFN-α-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has equivalent or reduced effects on divergent simian immunodeficiency viruses, and does not inhibit other retroviruses such as murine leukaemia virus. The Capsid region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step, with both the nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed. Finally, human MX1 (also known as MXA), a closely related protein that has long been recognized as a broadly acting inhibitor of RNA and DNA viruses, including the orthomyxovirus influenza A virus15,16, does not affect HIV-1, whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factor whose purposeful mobilization may represent a new therapeutic approach for the treatment of HIV/AIDS.

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Figure 1: Human MX2 is a potent inhibitor of HIV-1 infection.
Figure 2: MX2 is required for effective IFN-α-induced suppression of HIV-1.
Figure 3: MX2 inhibits the nuclear accumulation and integration of HIV-1 reverse transcripts.
Figure 4: Viral substrates for the human MX1 and MX2 proteins.

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Gene Expression Omnibus

Data deposits

The microarray methods and data are available under Gene Expression Omnibus GEO accession number GSE46599.

References

  1. Malim, M. H. & Bieniasz, P. D. HIV restriction factors and mechanisms of evasion. Cold Spring Harb. Perspect. Med. 2, a006940 (2012)

    Article  Google Scholar 

  2. Sheehy, A. M., Gaddis, N. C., Choi, J. D. & Malim, M. H. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646–650 (2002)

    Article  ADS  CAS  Google Scholar 

  3. Stremlau, M. et al. The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature 427, 848–853 (2004)

    Article  ADS  CAS  Google Scholar 

  4. 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  ADS  CAS  Google Scholar 

  5. 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 

  6. Hrecka, K. et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658–661 (2011)

    Article  CAS  Google Scholar 

  7. Laguette, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657 (2011)

    Article  CAS  Google Scholar 

  8. Asmuth, D. M. et al. Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial. J. Infect. Dis. 201, 1686–1696 (2010)

    Article  CAS  Google Scholar 

  9. Bitzegeio, J., Sampias, M., Bieniasz, P. D. & Hatziioannou, T. Adaptation to the interferon-induced antiviral state by human and simian immunodeficiency viruses. J. Virol. 87, 3549–3560 (2013)

    Article  CAS  Google Scholar 

  10. Goujon, C. & Malim, M. H. Characterization of the alpha interferon-induced postentry block to HIV-1 infection in primary human macrophages and T cells. J. Virol. 84, 9254–9266 (2010)

    Article  CAS  Google Scholar 

  11. Ho, D. D. et al. Recombinant human interferon alfa-A suppresses HTLV-III replication in vitro. Lancet 325, 602–604 (1985)

    Article  Google Scholar 

  12. Meylan, P. R., Guatelli, J. C., Munis, J. R., Richman, D. D. & Kornbluth, R. S. Mechanisms for the inhibition of HIV replication by interferons-α, -β, and -γ in primary human macrophages. Virology 193, 138–148 (1993)

    Article  CAS  Google Scholar 

  13. Pillai, S. K. et al. Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo. Proc. Natl Acad. Sci. USA 109, 3035–3040 (2012)

    Article  ADS  CAS  Google Scholar 

  14. Schoggins, J. W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011)

    Article  ADS  CAS  Google Scholar 

  15. Haller, O. & Kochs, G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J. Interferon Cytokine Res. 31, 79–87 (2011)

    Article  CAS  Google Scholar 

  16. Pavlovic, J., Zurcher, T., Haller, O. & Staeheli, P. Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J. Virol. 64, 3370–3375 (1990)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Goujon, C. et al. Evidence for IFNα-induced, SAMHD1-independent inhibitors of early HIV-1 infection. Retrovirology 10, 23 (2013)

    Article  CAS  Google Scholar 

  18. Sayah, D. M., Sokolskaja, E., Berthoux, L. & Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430, 569–573 (2004)

    Article  ADS  CAS  Google Scholar 

  19. Kim, B. H., Shenoy, A. R., Kumar, P., Bradfield, C. J. & MacMicking, J. D. IFN-inducible GTPases in host cell defense. Cell Host Microbe 12, 432–444 (2012)

    Article  CAS  Google Scholar 

  20. Gao, S. et al. Structure of myxovirus resistance protein a reveals intra- and intermolecular domain interactions required for the antiviral function. Immunity 35, 514–525 (2011)

    Article  CAS  Google Scholar 

  21. Mitchell, P. S. et al. Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA. Cell Host Microbe 12, 598–604 (2012)

    Article  CAS  Google Scholar 

  22. King, M. C., Raposo, G. & Lemmon, M. A. Inhibition of nuclear import and cell-cycle progression by mutated forms of the dynamin-like GTPase MxB. Proc. Natl Acad. Sci. USA 101, 8957–8962 (2004)

    Article  ADS  CAS  Google Scholar 

  23. Melén, K. et al. Human MxB protein, an interferon-α-inducible GTPase, contains a nuclear targeting signal and is localized in the heterochromatin region beneath the nuclear envelope. J. Biol. Chem. 271, 23478–23486 (1996)

    Article  Google Scholar 

  24. Brass, A. L. et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319, 921–926 (2008)

    Article  ADS  CAS  Google Scholar 

  25. König, R. et al. Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication. Cell 135, 49–60 (2008)

    Article  Google Scholar 

  26. Lee, K. et al. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe 7, 221–233 (2010)

    Article  CAS  Google Scholar 

  27. Shah, V. B. et al. The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. J. Virol. 87, 422–432 (2013)

    Article  CAS  Google Scholar 

  28. Pitossi, F. et al. A functional GTP-binding motif is necessary for antiviral activity of Mx proteins. J. Virol. 67, 6726–6732 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ponten, A., Sick, C., Weeber, M., Haller, O. & Kochs, G. Dominant-negative mutants of human MxA protein: domains in the carboxy-terminal moiety are important for oligomerization and antiviral activity. J. Virol. 71, 2591–2599 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Brass, A. L. et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell 139, 1243–1254 (2009)

    Article  Google Scholar 

  31. Adachi, A. et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59, 284–291 (1986)

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fouchier, R. A., Meyer, B. E., Simon, J. H., Fischer, U. & Malim, M. H. HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J. 16, 4531–4539 (1997)

    Article  CAS  Google Scholar 

  33. Simon, J. H., Southerling, T. E., Peterson, J. C., Meyer, B. E. & Malim, M. H. Complementation of vif-defective human immunodeficiency virus type 1 by primate, but not nonprimate, lentivirus vif genes. J. Virol. 69, 4166–4172 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Schindler, M. et al. Down-modulation of mature major histocompatibility complex class II and up-regulation of invariant chain cell surface expression are well-conserved functions of human and simian immunodeficiency virus nef alleles. J. Virol. 77, 10548–10556 (2003)

    Article  CAS  Google Scholar 

  35. Ochsenbauer, C. et al. Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. J. Virol. 86, 2715–2728 (2012)

    Article  CAS  Google Scholar 

  36. Ryan-Graham, M. A. & Peden, K. W. Both virus and host components are important for the manifestation of a Nef− phenotype in HIV-1 and HIV-2. Virology 213, 158–168 (1995)

    Article  CAS  Google Scholar 

  37. Sauter, D. et al. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host Microbe 6, 409–421 (2009)

    Article  CAS  Google Scholar 

  38. Soares, M. A. et al. A full-length and replication-competent proviral clone of SIVAGM from tantalus monkeys. Virology 228, 394–399 (1997)

    Article  CAS  Google Scholar 

  39. Sakai, H. et al. Genetic characterization of simian immunodeficiency virus isolated from an African mandrill. Arch. Virol. 125, 1–14 (1992)

    Article  CAS  Google Scholar 

  40. Gaddis, N. C. et al. Further investigation of simian immunodeficiency virus Vif function in human cells. J. Virol. 78, 12041–12046 (2004)

    Article  CAS  Google Scholar 

  41. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996)

    Article  ADS  CAS  Google Scholar 

  42. Mangeot, P. E. et al. High levels of transduction of human dendritic cells with optimized SIV vectors. Mol. Ther. 5, 283–290 (2002)

    Article  CAS  Google Scholar 

  43. Saenz, D. T., Teo, W., Olsen, J. C. & Poeschla, E. M. Restriction of feline immunodeficiency virus by Ref1, Lv1, and primate TRIM5α proteins. J. Virol. 79, 15175–15188 (2005)

    Article  CAS  Google Scholar 

  44. O'Rourke, J. P., Newbound, G. C., Kohn, D. B., Olsen, J. C. & Bunnell, B. A. Comparison of gene transfer efficiencies and gene expression levels achieved with equine infectious anemia virus- and human immunodeficiency virus type 1-derived lentivirus vectors. J. Virol. 76, 1510–1515 (2002)

    Article  CAS  Google Scholar 

  45. Jarrosson-Wuilleme, L. et al. Transduction of nondividing human macrophages with gammaretrovirus-derived vectors. J. Virol. 80, 1152–1159 (2006)

    Article  CAS  Google Scholar 

  46. Schaller, T. et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog. 7, e1002439 (2011)

    Article  CAS  Google Scholar 

  47. Cordeil, S. et al. Evidence for a different susceptibility of primate lentiviruses to type I interferons. J. Virol. 87, 2587–2596 (2013)

    Article  CAS  Google Scholar 

  48. Pear, W. S. et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92, 3780–3792 (1998)

    CAS  PubMed  Google Scholar 

  49. Mangeot, P. E. et al. Protein transfer into human cells by VSV-G-induced nanovesicles. Mol. Ther. 19, 1656–1666 (2011)

    Article  CAS  Google Scholar 

  50. Wei, X. et al. Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob. Agents Chemother. 46, 1896–1905 (2002)

    Article  CAS  Google Scholar 

  51. Shi, W., Oshlack, A. & Smyth, G. K. Optimizing the noise versus bias trade-off for Illumina whole genome expression BeadChips. Nucleic Acids Res. 38, e204 (2010)

    Article  Google Scholar 

  52. Markusic, D., Oude-Elferink, R., Das, A. T., Berkhout, B. & Seppen, J. Comparison of single regulated lentiviral vectors with rtTA expression driven by an autoregulatory loop or a constitutive promoter. Nucleic Acids Res. 33, e63 (2005)

    Article  Google Scholar 

  53. Trichas, G., Begbie, J. & Srinivas, S. Use of the viral 2A peptide for bicistronic expression in transgenic mice. BMC Biol. 6, 40 (2008)

    Article  Google Scholar 

  54. Donnelly, M. L. et al. Analysis of the aphthovirus 2A/2B polyprotein ‘cleavage’ mechanism indicates not a proteolytic reaction, but a novel translational effect: a putative ribosomal ‘skip’. J. Gen. Virol. 82, 1013–1025 (2001)

    Article  CAS  Google Scholar 

  55. Bamming, D. & Horvath, C. M. Regulation of signal transduction by enzymatically inactive antiviral RNA helicase proteins MDA5, RIG-I, and LGP2. J. Biol. Chem. 284, 9700–9712 (2009)

    Article  CAS  Google Scholar 

  56. Yee, J. K. et al. A general method for the generation of high-titer, pantropic retroviral vectors: highly efficient infection of primary hepatocytes. Proc. Natl Acad. Sci. USA 91, 9564–9568 (1994)

    Article  ADS  CAS  Google Scholar 

  57. Cauldwell, A. V., Moncorge, O. & Barclay, W. S. Unstable polymerase-nucleoprotein interaction is not responsible for avian influenza virus polymerase restriction in human cells. J. Virol. 87, 1278–1284 (2013)

    Article  CAS  Google Scholar 

  58. Neumann, G. & Hobom, G. Mutational analysis of influenza virus promoter elements in vivo. J. Gen. Virol. 76, 1709–1717 (1995)

    Article  CAS  Google Scholar 

  59. Pertel, T. et al. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472, 361–365 (2011)

    Article  ADS  CAS  Google Scholar 

  60. Newman, E. N. et al. Antiviral function of APOBEC3G can be dissociated from cytidine deaminase activity. Curr. Biol. 15, 166–170 (2005)

    Article  CAS  Google Scholar 

  61. O’Doherty, U., Swiggard, W. J., Jeyakumar, D., McGain, D. & Malim, M. H. A sensitive, quantitative assay for human immunodeficiency virus type 1 integration. J. Virol. 76, 10942–10950 (2002)

    Article  Google Scholar 

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Acknowledgements

We wish to thank L. Apolonia, A. Cimarelli, B. Hahn, T. Hatziioannou, J. Kappes, P. Mangeot, S. Papaioannou, N. Parrish, N. Sherer and C. Swanson for the provision of reagents and for discussions, and M. Mirza, E. Papouli, Q. Oscar Y. Li and G. Pacini for technical assistance. This work was supported by the UK Medical Research Council, the National Institutes of Health (DA033773), the European Commission’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. PIEF-GA-2009-237501 (to C.G.), a Wellcome Trust Research Training Fellowship (to T.D.) and the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust.

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Authors and Affiliations

  1. Department of Infectious Diseases, King’s College London, London SE1 9RT, UK,

    Caroline Goujon, Hélène Bauby, Tomas Doyle, Christopher C. Ward, Torsten Schaller & Michael H. Malim

  2. Division of Infectious Diseases, Section of Virology, Imperial College London, London W2 1PG, UK,

    Olivier Moncorgé & Wendy S. Barclay

  3. Division of Infection and Immunity, Centre for Medical Molecular Virology, University College London, London WC1 6RT, UK,

    Stéphane Hué

  4. Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK,

    Reiner Schulz

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  1. Caroline Goujon
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Contributions

C.G. and M.H.M. designed the study and wrote the manuscript. C.G. carried out the experiments. O.M. and W.S.B. designed and carried out the influenza A virus experiment. O.M., H.B., T.D., C.C.W., T.S. and S.H. provided technical assistance. R.S. performed the microarray analysis. All authors read and approved the final manuscript.

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Correspondence to Michael H. Malim.

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Extended data figures and tables

Extended Data Figure 1 MX2 inhibits infection with VSV-G-pseudotyped HIV-1.

U87-MG CD4+ CXCR4+ cells were transduced with EasiLV expressing the different candidate cDNAs, CD8, GFP or TRIMCyp cDNA controls and treated with doxycycline for 48 h, left untransduced (Ctrl) or treated with IFN-α for 24 h before infection. The cells were infected with increasing viral inputs of VSV-G-pseudotyped NL4-3/Nef-IRES-Renilla (0.04–5 ng p24Gag) and infection efficiency was monitored at 48 h by measuring Renilla activity. Mean relative infection efficiencies from four independent experiments are shown.

Extended Data Figure 2 MX2 is active in other cell types.

a, CEM-SS cells were transduced with EasiLV expressing CD8 or MX2 and treated with doxycycline for 4–5 days and infected with increasing viral inputs of VSV-G-pseudotyped NL4-3/Nef-IRES-GFP (0.2–25 ng p24Gag). The efficiency of infection was measured at 72 h by scoring the percentage of GFP-expressing cells, among the E2-Crimson-expressing cells, by flow cytometry. Mean percentages of infected cells from independent duplicates are shown. b, 293T cells were transduced with lentiviral vectors containing a bicistronic expression cassette for either CD8 or MX2 with the puromycinR gene, and selected for puromycin resistance. Transduced cells were infected with increasing viral inputs of VSV-G-pseudotyped NL4-3/Nef-IRES-Renilla (0.2–25 ng p24Gag) and Renilla activity was measured at 48 h. Mean relative infection efficiencies from three independent experiments are shown.

Extended Data Figure 3 MX2 relative levels of expression and IFN-α-inducibility.

RNA was extracted from control (Ctrl) or IFN-α-treated (IFNα) PMA-treated or dividing THP-1 cells, MDMs, primary CD4+ T cells, U87-MG, HT1080, CEM, CEM-SS, HUT78 and Jurkat cells. 500-ng aliquots of RNA were reverse transcribed and the levels of MX2, as well as ISG15, and two endogenous controls, GAPDH and β-actin (ACTB), were analysed by qRT–PCR. The graph shows the mean of relative levels of expression (normalized to both endogenous controls and compared to THP-1 without IFN-α treatment) obtained in three independent experiments.

Extended Data Figure 4 MX2 participates in IFN-α-induced resistance to HIV-1 in monocytic THP-1 cells.

a, THP-1 cells expressing a control shRNA or two different shRNAs targeting MX2 were treated with or without IFN-α (500 U ml−1) for 24 h. Cells were infected with five different doses of NL4-3/Nef-IRES-Renilla (0.04–25 ng p24Gag) for 48 h, and Renilla activity was measured. Mean relative infection efficiencies from two independent experiments are shown. b, Immunoblot analysis of parallel samples from a. Protein levels of MX2 and APOBEC3G (A3G, positive control for IFN-α treatment) were determined, and tubulin served as a loading control.

Extended Data Figure 5 MX2 blocks productive HIV-1IIIB infection.

U87-MG CD4+ CXCR4+ cells were transduced with EasiLV expressing CD8 or MX2 and treated with doxycycline for 48 h, left untransduced (Ctrl) or treated with IFN-α for 24 h before infection. Increasing viral inocula (indicated in ng p24Gag) were used to infect the cells with HIV-1IIIB. The levels of infection were analysed at 48 h by measuring the percentage of cells expressing p24Gag after intracellular staining. The means of three independent experiments are shown. This analysis accompanies the experiments shown in Fig. 3.

Extended Data Figure 6 Expression of wild-type and GTPase domain mutants of MX1 and MX2.

Immunoblot analysis of parallel samples from Fig. 4e. Protein levels of Flag-tagged MX1 and MX2 proteins were determined using a Flag-specific antibody and tubulin served as a loading control.

Extended Data Table 1 Candidate genes
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Goujon, C., Moncorgé, O., Bauby, H. et al. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502, 559–562 (2013). https://doi.org/10.1038/nature12542

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