title: Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction.
abstract: Primate lentiviruses encode four "accessory proteins" including Vif, Vpu, Nef, and Vpr/Vpx. Vif and Vpu counteract the antiviral effects of cellular restrictions to early and late steps in the viral replication cycle. We present evidence that the Vpx proteins of HIV-2/SIV(SM) promote virus infection by antagonizing an antiviral restriction in macrophages. Fusion of macrophages in which Vpx was essential for virus infection, with COS cells in which Vpx was dispensable for virus infection, generated heterokaryons that supported infection by wild-type SIV but not Vpx-deleted SIV. The restriction potently antagonized infection of macrophages by HIV-1, and expression of Vpx in macrophages in trans overcame the restriction to HIV-1 and SIV infection. Vpx was ubiquitylated and both ubiquitylation and the proteasome regulated the activity of Vpx. The ability of Vpx to counteract the restriction to HIV-1 and SIV infection was dependent upon the HIV-1 Vpr interacting protein, damaged DNA binding protein 1 (DDB1), and DDB1 partially substituted for Vpx when fused to Vpr. Our results indicate that macrophage harbor a potent antiviral restriction and that primate lentiviruses have evolved Vpx to counteract this restriction.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Natalia
authors.initials: N
authors.lastname: Sharova
authors.forename: Yuanfei
authors.initials: Y
authors.lastname: Wu
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhu
authors.forename: Ruzena
authors.initials: R
authors.lastname: Stranska
authors.forename: Rajnish
authors.initials: R
authors.lastname: Kaushik
authors.forename: Mark
authors.initials: M
authors.lastname: Sharkey
authors.forename: Mario
authors.initials: M
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D015498:HIV-2 / Q000472:pathogenicity / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000821:virology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C074286:VPX protein, Human immunodeficiency virus 2; D054334:Viral Regulatory and Accessory Proteins