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HIV-2/SIV viral protein X counteracts HUSH repressor complex
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Journal Article
HIV-2/SIV viral protein X counteracts HUSH repressor complex
2018
Overview
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 variegation
3
. 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.
Viral protein X from HIV-2/SIV targets the HUSH (TASOR, MPP8 and periphilin) complex for proteasomal degradation through recruitment of the DCAF1 ubiquitin ligase adaptor, enabling reactivation of latent proviruses.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/89
/ 38/22
/ 82/1
/ 82/29
/ 82/58
/ 96/31
/ Biomedical and Life Sciences
/ HIV
/ Human immunodeficiency virus
/ Letter
/ Microbiology and Parasitology
/ Proteins
/ Virology
/ Vpr gene
