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: Natalia Sharova, Yuanfei Wu, Xiaonan Zhu, Ruzena Stranska, Rajnish Kaushik, Mark Sharkey, Mario Stevenson
• Journal: PLoS pathogens (PLoS Pathog) Vol. 4 Issue 5 Pg. e1000057 (May 02 2008) ISSN: 1553-7374 [Electronic] United States
• PMID: 18451984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DDB1 protein, human
• DNA-Binding Proteins
• RNA, Small Interfering
• Recombinant Fusion Proteins
• VPX protein, Human immunodeficiency virus 2
• Viral Regulatory and Accessory Proteins

Topics

• Animals
• COS Cells
• Chlorocebus aethiops
• DNA-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation, Viral
• Gene Silencing
• HIV-2 (pathogenicity, physiology)
• Leukocytes, Mononuclear (metabolism, virology)
• Macrophages (virology)
• RNA Interference
• RNA, Small Interfering (genetics)
• Recombinant Fusion Proteins (genetics, metabolism)
• Viral Regulatory and Accessory Proteins (genetics, metabolism)