Program in Molecular Medicine
Animals; COS Cells; Cercopithecus aethiops; DNA-Binding Proteins; Gene Expression Regulation, Viral; Gene Silencing; HIV-2; Leukocytes, Mononuclear; Macrophages; RNA Interference; RNA, Small Interfering; Recombinant Fusion Proteins; Viral Regulatory and Accessory Proteins
Life Sciences | Medicine and Health Sciences
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.
Rights and Permissions
Copyright: © 2008 Sharova et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS Pathog. 2008 May 2;4(5):e1000057. Link to article on publisher's site
Sharova, Natalia; Wu, Yuanfei; Zhu, Xiaochun; Stranska, Ruzena; Kaushik, Rachna; Sharkey, Mark E.; and Stevenson, Mario, "Primate lentiviral Vpx commandeers DDB1 to counteract a macrophage restriction" (2008). Open Access Articles. 2029.