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Nat Microbiol. 2018 Aug;3(8):891-897. doi: 10.1038/s41564-018-0179-6. Epub 2018 Jun 11.

HIV-2/SIV viral protein X counteracts HUSH repressor complex.

Chougui G1,2,3, Munir-Matloob S1,2,3, Matkovic R1,2,3, Martin MM1,2,3, Morel M1,2,3, Lahouassa H1,2,3, Leduc M1,2,3,4, Ramirez BC1,2,3, Etienne L5,6,7, Margottin-Goguet F8,9,10.

Author information

1
Inserm, U1016, Institut Cochin, Paris, France.
2
CNRS, UMR8104, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
3P5 Proteomic Facility of Université Paris Descartes , Paris, France.
5
CIRI - International Center for Infectiology Research, Inserm U1111, Lyon, France.
6
CNRS UMR5308, Lyon, France.
7
Ecole Normale Supérieure de Lyon, Université Claude Bernard Lyon 1, Lyon, France.
8
Inserm, U1016, Institut Cochin, Paris, France. florence.margottin-goguet@inserm.fr.
9
CNRS, UMR8104, Paris, France. florence.margottin-goguet@inserm.fr.
10
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. florence.margottin-goguet@inserm.fr.

Abstract

To evade host immune defences, human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) have evolved auxiliary proteins that target cell restriction factors. Viral protein X (Vpx) from the HIV-2/SIVsmm lineage enhances viral infection by antagonizing SAMHD1 (refs 1,2), but this antagonism is not sufficient to explain all Vpx phenotypes. Here, through a proteomic screen, we identified another Vpx target-HUSH (TASOR, MPP8 and periphilin)-a complex involved in position-effect variegation3. HUSH downregulation by Vpx is observed in primary cells and HIV-2-infected cells. Vpx binds HUSH and induces its proteasomal degradation through the recruitment of the DCAF1 ubiquitin ligase adaptor, independently from SAMHD1 antagonism. As a consequence, Vpx is able to reactivate HIV latent proviruses, unlike Vpx mutants, which are unable to induce HUSH degradation. Although antagonism of human HUSH is not conserved among all lentiviral lineages including HIV-1, it is a feature of viral protein R (Vpr) from simian immunodeficiency viruses (SIVs) of African green monkeys and from the divergent SIV of l'Hoest's monkey, arguing in favour of an ancient lentiviral species-specific vpx/vpr gene function. Altogether, our results suggest the HUSH complex as a restriction factor, active in primary CD4+ T cells and counteracted by Vpx, therefore providing a molecular link between intrinsic immunity and epigenetic control.

PMID:
29891865
DOI:
10.1038/s41564-018-0179-6

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