The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation

The endosomal sorting complexes required for transport (escrt) machinery,a highly conserved set of four hetero-oligomeric protein complexes,is required for multivesicular body formation,sorting ubiquitinylated membrane proteins for lysosomal degradation,cytokinesis and the final stages of assembly of a number of enveloped viruses,including the human immunodeficiency viruses. here,we show an additional role for the escrt machinery in hiv-1 release. bst-2/tetherin is a restriction factor that impedes hiv release by tethering mature virus particles to the plasma membrane. we found that hrs,a key component of the escrt-0 complex,promotes efficient release of hiv-1 and that sirna-mediated hrs depletion induces a bst-2/tetherin phenotype. this activity is related to the ability of the hiv-1 vpu protein to down-regulate bst-2/tetherin. we found that bst-2/tetherin undergoes constitutive escrt-dependent sorting for lysosomal degradation and that this degradation is enhanced by vpu expression. we demonstrate that vpu-mediated bst-2/tetherin down-modulation and degradation require hrs (escrt-0) function and that knock down of hrs increases cellular levels of bst-2/tetherin and restricts virus release. furthermore,hrs co-precipitates with vpu and bst-2. our results provide further insight into the mechanism by which vpu counteracts bst-2/tetherin and promotes hiv-1 dissemination,and they highlight an additional role for the escrt machinery in virus release. © 2011 janvier et al.