Macrophages and dendritic cells have key roles in viral infections, providing virus reservoirs that frequently resist antiviral therapies and linking innate virus detection to antiviral adaptive immune responses1,2. Human immunodeficiency virus 1 (HIV-1) fails to transduce dendritic cells and has a reduced ability to transduce macrophages, due to an as yet uncharacterized mechanism that inhibits infection by interfering with efficient synthesis of viral complementary DNA3,4. In contrast, HIV-2 and related simian immunodeficiency viruses (SIVsm/mac) transduce myeloid cells efficiently owing to their virion-associated Vpx accessory proteins, which counteract the restrictive mechanism5,6. Here we show that the inhibition of HIV-1 infection in macrophages involves the cellular SAM domain HD domain-containing protein 1 (SAMHD1). Vpx relieves the inhibition of lentivirus infection in macrophages by loading SAMHD1 onto the CRL4DCAF1 E3 ubiquitin ligase, leading to highly efficient proteasome-dependent degradation of the protein. Mutations in SAMHD1 cause Aicardi–Goutières syndrome, a disease that produces a phenotype that mimics the effects of a congenital viral infection7,8. Failure to dispose of endogenous nucleic acid debris in Aicardi–Goutières syndrome results in inappropriate triggering of innate immune responses via cytosolic nucleic acids sensors9,10. Thus, our findings show that macrophages are defended from HIV-1 infection by a mechanism that prevents an unwanted interferon response triggered by self nucleic acids, and uncover an intricate relationship between innate immune mechanisms that control response to self and to retroviral pathogens.
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We thank the Karn, McDonald and Bernstein laboratories, C. Carlin, R. Asaad, M. Reuter and A. Valentin-Torres, for reagents and help at various stages of this project. We acknowledge the excellent assistance of C. Wang with fluorescence microscopy. We also thank M. Emerman and N. Manel for HIV-2 Rod proviral constructs, F. Kirchhoff for the SIVmac 239-GFP proviral clone, M. Lederman and D. McDonald for discussions, J. Karn and M. Greenberg for discussions and comments on the manuscript. We are grateful to L. Van Aelst and D. Littman for advice, discussions and critical reading of the manuscript. This work in the J.S. laboratory was supported by NIH grants R01 AI077459 and R21 AI084694 and by Case CFAR developmental funds. S.K.S., L.F. and M.P.W. are supported by The Stowers Institute for Medical Research.
The authors declare no competing financial interests.
The RAW mass spectrometry and SEQUEST results files for the MudPIT analyses reported in Supplementary Table I may be downloaded from ProteomeCommons.org Tranche using the following hash: +qNEgtnB3fXlq2awdE8X67zEY8D2mQbK/tYXKaA1lWve32mRnGBMOZ3Lkoy+y9HeooRuLwE8aIvPMYEx9xqBDzciIscAAAAAAAAK0w==. This data can be accessed using the passphrase Hrecka&SAMHD1.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. Readers are welcome to comment on the online version of this article at www.nature.com/nature. Correspondence and requests for materials should be addressed to J.S. (email@example.com).
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Hrecka, K., Hao, C., Gierszewska, M. et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature 474, 658–661 (2011). https://doi.org/10.1038/nature10195
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