Characterization of the SAMHD1-mediated restriction to lentiviral infection counteracted by Vpx and analyzing its role in innate immunity

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Non-structural proteins have emerged as key players for lentiviruses in their battle with the host immune system. Viruses of the HIV-2/SIVmac/SIVsm lineage encode, in addition to its close relative Vpr, the non-structural protein Vpx. Vpx, but not Vpr facilitates the SIV and HIV-1 infection of monocyte-derived macrophages (MDM) and dendritic cells (DC), where it has been proposed to neutralize an unknown restriction factor. Recently, SAMHD1 has been identified as the putative restriction factor and linked to the Vpx phenotype. The mechanism of the myeloid restriction is not clear but the importance of the phosphohydrolase domain suggests that its putative nuclease activity might be key. Since SAMHD1 is expressed in divergent cell lines, it is most likely not determining the myeloid cell specificity of the block. This project will use gene transfer and proteomics approaches to identify potential myeloid cell specific cofactors of SAMHD1. We will also characterize the mechanism of the SAMHD1 block and analyze the binding of Vpx to SAMHD1. It has been reported that overcoming this block by Vpx triggers an innate immune response to HIV-1 in DC. We will determine whether this effect is unique to DC or whether it is also present in MDM, which are main target cells of HIV-1 in vivo. Understanding this immune response and the role of Vpx in infection might answer the question why HIV-1 encodes only Vpr and not Vpx. The Vpx-SAMHD1 interaction will also provide clues to Vpr, which most likely functions through a similar pathway. The insights on the role of Vpx and Vpr in innate immunity may unearth a vulnerable step in infection that could be targeted by antiviral drug development.