Abstract
BackgroundVpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys). HIV-2 and SIVMAC, zoonoses resulting from SIVSM transmission to humans or Asian rhesus macaques (Macaca mulatta), also encode Vpx. In myeloid cells, Vpx promotes reverse transcription and transduction by these viruses. This activity correlates with Vpx binding to DCAF1 (VPRBP) and association with the DDB1/RBX1/CUL4A E3 ubiquitin ligase complex. When delivered experimentally to myeloid cells using VSV G-pseudotyped virus-like particles (VLPs), Vpx promotes reverse transcription of retroviruses that do not normally encode Vpx.ResultsHere we show that Vpx has the extraordinary ability to completely rescue HIV-1 transduction of human monocyte-derived dendritic cells (MDDCs) from the potent antiviral state established by prior treatment with exogenous type 1 interferon (IFN). The magnitude of rescue was up to 1,000-fold, depending on the blood donor, and was also observed after induction of endogenous IFN and IFN-stimulated genes (ISGs) by LPS, poly(I:C), or poly(dA:dT). The effect was relatively specific in that Vpx-associated suppression of soluble IFN-β production, of mRNA levels for ISGs, or of cell surface markers for MDDC differentiation, was not detected. Vpx did not rescue HIV-2 or SIVMAC transduction from the antiviral state, even in the presence of SIVMAC or HIV-2 VLPs bearing additional Vpx, or in the presence of HIV-1 VLPs bearing all accessory genes. In contrast to the effect of Vpx on transduction of untreated MDDCs, HIV-1 rescue from the antiviral state was not dependent upon Vpx interaction with DCAF1 or on the presence of DCAF1 within the MDDC target cells. Additionally, although Vpx increased the level of HIV-1 reverse transcripts in MDDCs to the same extent whether or not MDDCs were treated with IFN or LPS, Vpx rescued a block specific to the antiviral state that occurred after HIV-1 cDNA penetrated the nucleus.ConclusionVpx provides a tool for the characterization of a potent, new HIV-1 restriction activity, which acts in the nucleus of type 1 IFN-treated dendritic cells.
Highlights
Vpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys)
When immature monocyte-derived dendritic cells (MDDCs) were challenged with three-part, HIV-1-GFP reporter virus, pseudotyped with vesicular stomatitis virus glycoprotein (VSV G), SIVMAC virus-like particles (VLPs) increased transduction efficiency 3- to 10-fold (Figure 1A, upper panels), depending upon the multiplicity of infection
The experiments presented here demonstrate that SIVMAC/HIV-2 Vpx rescues HIV-1 from the antiviral state established by exogenous type I IFN or LPS in MDDCs
Summary
Vpx is a virion-associated protein encoded by SIVSM, a lentivirus endemic to the West African sooty mangabey (Cercocebus atys). HIV-2 and SIVMAC, zoonoses resulting from SIVSM transmission to humans or Asian rhesus macaques (Macaca mulatta), encode Vpx. In myeloid cells, Vpx promotes reverse transcription and transduction by these viruses. When delivered experimentally to myeloid cells using VSV Gpseudotyped virus-like particles (VLPs), Vpx promotes reverse transcription of retroviruses that do not normally encode Vpx. In addition to the gag, pol, and env genes common to all retroviruses, lentiviruses including HIV-1 bear specialized genes such as vpr that contribute to viral replication and pathogenesis [1]. Simian immunodeficiency viruses isolated from West African sooty mangabeys (SIVSM) possess vpr as well as a highly homologous gene called vpx. Myeloid cells are believed to be critical targets for lentiviruses in vivo, partly because they are capable of productive infection, and because they facilitate virus transmission to CD4+ T-cells [16,17,18]
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