Primate Lentiviral Vpx Commandeers DDB1 to Counteract a Macrophage Restriction

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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/SIVSM 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. Defense against infection by the primate lentiviruses HIV/SIV is mediated primarily by antibodies that can neutralize the virus and by cytotoxic cells that can recognize and kill other virus-infected cells. However, in the past several years, research has revealed the existence of an additional line of host defense against HIV/SIV. It is now apparent that cells contain factors (also known as cellular restrictions) that potently inhibit virus infection. This has forced primate lentiviruses to evolve a strategy to counteract these cellular restriction factors. For example, HIV/SIV encode an accessory protein called Vif, whose function is to neutralize a cellular restriction to HIV/SIV infection. Our study provides evidence for a novel restriction that is expressed by macrophages and which potently antagonizes HIV and SIV infection. We describe how the virus protects itself from this cellular restriction. The goal is to harness this cellular restriction as the basis for a novel therapeutic strategy against HIV infection.