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

Nature volume 474, pages 654–657 (2011)Cite this article

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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.

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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.

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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.

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Affiliations

  1. Institut de Génétique Humaine, Laboratoire de Virologie Moléculaire, CNRS UPR1142, Montpellier 34000 France

    Nadine Laguette, Bijan Sobhian, Mathieu Ringeard, Christine Chable-Bessia, Ahmad Yatim & Monsef Benkirane

  2. Institut Pasteur, Virus and Immunity Unit, URA CNRS 3015, Paris, France

    Nicoletta Casartelli & Olivier Schwartz

  3. Institut Cochin, Université Paris Descartes, CNRS UMR 8104 INSERM U567, Paris, France

    Emmanuel Ségéral & Stéphane Emiliani

Authors
  1. Nadine Laguette
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  2. Bijan Sobhian
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  3. Nicoletta Casartelli
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  4. Mathieu Ringeard
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  5. Christine Chable-Bessia
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  6. Emmanuel Ségéral
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  7. Ahmad Yatim
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  8. Stéphane Emiliani
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  9. Olivier Schwartz
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  10. Monsef Benkirane
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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.

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The authors declare no competing financial interests.

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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

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