Replication of HIV-1 and other retroviruses is dependent on numerous host proteins in the cells. Some of the host proteins, however, function as restriction factors to block retroviral infection of target cells. The host protein SAMHD1 has been identified as the first mammalian deoxynucleoside triphosphate triphosphohydrolase (dNTPase), which blocks the infection of HIV-1 and other retroviruses in non-cycling immune cells. SAMHD1 protein is highly expressed in human myeloid-lineage cells and CD4+ T-lymphocytes, but its retroviral restriction function is only observed in noncycling cells. Recent studies have revealed biochemical mechanisms of SAMHD1-mediated retroviral restriction. In this review, the latest progress on SAMHD1 research is summarized and the mechanisms by which SAMHD1 mediates retroviral restriction are analyzed. Although the physiological function of SAMHD1 is largely unknown, this review provides perspectives about the role of endogenous SAMHD1 protein in maintaining normal cellular function, such as nucleic acid metabolism and the proliferation of cells. 1. Introduction HIV-1 infection of human target cells is highly dependent on numerous host proteins to support viral replication [1, 2]. Genome-wide functional screens of HIV-1 cofactors have revealed that over two hundreds of human proteins are required for efficient HIV-1 replication in the cells [3–6]. However, during the long history of host-retrovirus interactions, primates including humans have evolved intrinsic immunity to defend against viral infection through host proteins called restriction factors, which often can be counteracted by viral proteins via intracellular degradation [7–9]. Studying those host restriction factors not only helps define the unique function of certain viral proteins in the infection and viral pathogenesis but also provides new insights into developing more effective intervention strategies to block retroviral infections. The major HIV-1 target cells supporting viral replication are activated CD4+ T-lymphocytes [10], while other cell types such as primary monocytes, dendritic cells (DCs), and macrophages also contribute to initial infection and viral transmission [11, 12]. Nondividing CD4+ T-lymphocytes and myeloid cells including monocytes, DCs, and macrophages play an important role in establishment of HIV-1 initial infection and viral transmission [10, 11]. However, these cells are refractory to postentry HIV-1 infection due to multifaceted cellular mechanisms [11, 12]. Resting CD4+ T-cells are essential for the establishment and maintenance of
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