Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx

This article has been updated

Abstract

The primate lentivirus auxiliary protein Vpx counteracts an unknown restriction factor that renders human dendritic and myeloid cells largely refractory to HIV-1 infection1,2,3,4,5,6. Here we identify SAMHD1 as this restriction factor. SAMHD1 is a protein involved in Aicardi–Goutières syndrome, a genetic encephalopathy with symptoms mimicking congenital viral infection, that has been proposed to act as a negative regulator of the interferon response7. We show that Vpx induces proteasomal degradation of SAMHD1. Silencing of SAMHD1 in non-permissive cell lines alleviates HIV-1 restriction and is associated with a significant accumulation of viral DNA in infected cells. Concurrently, overexpression of SAMHD1 in sensitive cells inhibits HIV-1 infection. The putative phosphohydrolase activity of SAMHD1 is probably required for HIV-1 restriction. Vpx-mediated relief of restriction is abolished in SAMHD1-negative cells. Finally, silencing of SAMHD1 markedly increases the susceptibility of monocytic-derived dendritic cells to infection. Our results demonstrate that SAMHD1 is an antiretroviral protein expressed in cells of the myeloid lineage that inhibits an early step of the viral life cycle.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: SAMHD1 interacts with Vpx and is degraded by the proteasome.
Figure 2: SAMHD1 restricts HIV-1 infection in THP-1 cells.
Figure 3: SAMHD1 restricts HIV-1 infection in primary MDDCs.

Change history

  • 29 June 2011

    The received date has been corrected online from 10 March 2010 to 10 March 2011.

References

  1. Goujon, C. et al. Characterization of simian immunodeficiency virus SIVSM/human immunodeficiency virus type 2 Vpx function in human myeloid cells. J. Virol. 82, 12335–12345 (2008)

    CAS  Article  Google Scholar 

  2. Goujon, C. et al. SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent restriction pathway present in human dendritic cells. Retrovirology 4, 2 (2007)

    Article  Google Scholar 

  3. Hirsch, V. M. et al. Vpx is required for dissemination and pathogenesis of SIVSM PBj: evidence of macrophage-dependent viral amplification. Nature Med. 4, 1401–1408 (1998)

    CAS  Article  Google Scholar 

  4. Kaushik, R., Zhu, X., Stranska, R., Wu, Y. & Stevenson, M. A cellular restriction dictates the permissivity of nondividing monocytes/macrophages to lentivirus and gammaretrovirus infection. Cell Host Microbe 6, 68–80 (2009)

    CAS  Article  Google Scholar 

  5. Sharova, N. et al. Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction. PLoS Pathog. 4, e1000057 (2008)

    Article  Google Scholar 

  6. Ayinde, D., Maudet, C., Transy, C. & Margottin-Goguet, F. Limelight on two HIV/SIV accessory proteins in macrophage infection: is Vpx overshadowing Vpr? Retrovirology 7, 35 (2010)

    Article  Google Scholar 

  7. Rice, G. I. et al. Mutations involved in Aicardi-Goutieres syndrome implicate SAMHD1 as regulator of the innate immune response. Nature Genet. 41, 829–832 (2009)

    CAS  Article  Google Scholar 

  8. Nakatani, Y. & Ogryzko, V. Immunoaffinity purification of mammalian protein complexes. Methods Enzymol. 370, 430–444 (2003)

    CAS  Article  Google Scholar 

  9. Bergamaschi, A. et al. The human immunodeficiency virus type 2 Vpx protein usurps the CUL4A–DDB1 DCAF1 ubiquitin ligase to overcome a postentry block in macrophage infection. J. Virol. 83, 4854–4860 (2009)

    CAS  Article  Google Scholar 

  10. Srivastava, S. et al. Lentiviral Vpx accessory factor targets VprBP/DCAF1 substrate adaptor for cullin 4 E3 ubiquitin ligase to enable macrophage infection. PLoS Pathog. 4, e1000059 (2008)

    Article  Google Scholar 

  11. Li, N., Zhang, W. & Cao, X. Identification of human homologue of mouse IFN-γ induced protein from human dendritic cells. Immunol. Lett. 74, 221–224 (2000)

    CAS  Article  Google Scholar 

  12. Liao, W., Bao, Z., Cheng, C., Mok, Y. K. & Wong, W. S. Dendritic cell-derived interferon-γ-induced protein mediates tumor necrosis factor-α stimulation of human lung fibroblasts. Proteomics 8, 2640–2650 (2008)

    CAS  Article  Google Scholar 

  13. Zhao, D., Peng, D., Li, L., Zhang, Q. & Zhang, C. Inhibition of G1P3 expression found in the differential display study on respiratory syncytial virus infection. Virol. J. 5, 114 (2008)

    Article  Google Scholar 

  14. Zimmerman, M. D., Proudfoot, M., Yakunin, A. & Minor, W. Structural insight into the mechanism of substrate specificity and catalytic activity of an HD-domain phosphohydrolase: the 5′-deoxyribonucleotidase YfbR from Escherichia coli . J. Mol. Biol. 378, 215–226 (2008)

    CAS  Article  Google Scholar 

  15. Gramberg, T., Sunseri, N. & Landau, N. R. Evidence for an activation domain at the amino terminus of simian immunodeficiency virus Vpx. J. Virol. 84, 1387–1396 (2010)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  17. 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)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  19. Altfeld, M., Fadda, L., Frleta, D. & Bhardwaj, N. DCs and NK cells: critical effectors in the immune response to HIV-1. Nature Rev. Immunol. 11, 176–186 (2011)

    CAS  Article  Google Scholar 

  20. Yan, N. & Lieberman, J. Gaining a foothold: how HIV avoids innate immune recognition. Curr. Opin. Immunol. 23, 21–28 (2011)

    CAS  Article  Google Scholar 

  21. Manel, N. et al. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467, 214–217 (2010)

    ADS  CAS  Article  Google Scholar 

  22. Borrow, P., Shattock, R. J. & Vyakarnam, A. Innate immunity against HIV: a priority target for HIV prevention research. Retrovirology 7, 84 (2010)

    Article  Google Scholar 

  23. Cobb, A. et al. Development of a HIV-1 lipopeptide antigen pulsed therapeutic dendritic cell vaccine. J. Immunol. Methods 365, 27–37 (2011)

    CAS  Article  Google Scholar 

  24. Lepelley, A. et al. Innate sensing of HIV-infected cells. PLoS Pathog. 7, e1001284 (2011)

    CAS  Article  Google Scholar 

  25. Blanchet, F. P. et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity 32, 654–669 (2010)

    CAS  Article  Google Scholar 

  26. Kumar, D., Shadrach, J. L., Wagers, A. J. & Lassar, A. B. Id3 is a direct transcriptional target of Pax7 in quiescent satellite cells. Mol. Biol. Cell 20, 3170–3177 (2009)

    CAS  Article  Google Scholar 

  27. Sobhian, B. et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol. Cell 38, 439–451 (2010)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We wish to thank members of the Molecular Virology laboratory for critical reading of the manuscript, N. Manel for SIV3+ molecular clone and J. Luban for SIV delta Vpx and Vpx mutants. This work was supported by grants from the ERC (250333), Sidaction, ANRS and FRM ‘équipe labéllisée’ to M.B. N.L was supported by ANRS and SIDACTION fellowships; B.S. by ANRS fellowship; M.R. by CNRS/région Languedoc Roussillon fellowship. O.S. and N.C. are supported by grants from ANRS, Sidaction, ANR, European FP7 contract 201412 and Institut Pasteur.

Author information

Authors and Affiliations

Authors

Contributions

M.B. and N.L. conceived the study and wrote the paper. M.B. and N.L. designed experiments and interpreted data. O.S. designed some experiments, interpreted data and edited the paper. N.L., B.S., N.C. and M.R. designed and performed experiments. C.C.-B. and E.S. provided technical assistance. N.L., B.S., N.C., M.B., A.Y., S.E. and O.S. discussed the data.

Corresponding authors

Correspondence to Nadine Laguette or Monsef Benkirane.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-10 with legends. (PDF 392 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Laguette, N., Sobhian, B., Casartelli, N. et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counteracted by Vpx. Nature 474, 654–657 (2011). https://doi.org/10.1038/nature10117

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10117

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing