The dNTP triphosphohydrolase SAMHD1 is a host restriction factor able to limit HIV-1 infection. HIV-2 and SIVsm lineage viruses counteract SAMHD1-mediated restriction by encoding the viral accessory protein Vpx, which triggers the proteasomal degradation of SAMHD1. Although HIV-1 doesn´t encode Vpx, its infection can be enhanced in macrophages (Mac) by adding Vpx-containing virus-like particles (VLP). However, in dendritic cells (DC), when the SAMHD1 restriction of HIV-1 is alleviated by delivery of Vpx, HIV-1 sensing promotes an innate immune response, suggesting that HIV-1 might sacrifice a more efficient infection of its target cells to avoid its sensing by intrinsic immunity in DCs. Therefore, we hypothesized that molecules able to block the dNTP triphosphohydrolase activity of SAMHD1 would activate this immune response. Thus, we generated peptides targeting the tetramer interface of SAMHD1 and already identified a peptide that interferes with its activity in vitro. Refined peptides, based on the lead molecule, have been synthesized and will be further assessed in an in vitro dNTPase assay. Additionally, a small molecules library will be tested in this assay in order to identify other potential inhibitor candidates. Subsequently, we will determine the ability of active candidates to revoke the SAMHD1-mediated restriction in HIV infectivity assays in myeloid cell lines and primary cells. Next, we will also evaluate their effect on the innate immune response upon HIV-1 infection. Finally, we will analyse the impact of blocking SAMHD1 in DCs on the induction of antiviral immune response in vivo. Altogether, this study will allow the identification of SAMHD1 inhibitors and will evaluate the ability of these molecules to promote an enhanced antiviral immune response upon HIV infection.