Enhancing antiviral immunity by blocking SAMHD1 activity and targeting viral immune evasion
The dNTP triphosphohydrolase SAMHD1 is a host restriction factor that limits HIV-1 infection in non-dividing myeloid cells. In contrast to HIV-1, HIV-2 and related SIVs encode the viral accessory protein Vpx that counteracts SAMHD1 by initiating its proteasomal degradation, which is essential for efficient HIV-2 and SIV infection of macrophages and dendritic cells (DCs). Preincubation of macrophages and DCs with Vpx containing virus-like particles does not only enhance the infection of SIV and HIV-2 but also of HIV-1. Moreover, the Vpx-mediated enhancement of HIV-1 infection triggers an innate immune response in DCs, 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 blocking SAMHD1 activate this immune response to HIV infection. Thus, we have generated peptides that specifically target the tetramer interface of SAMHD1 and have already identified a peptide that interferes with SAMHD1 activity in vitro. Based on the lead peptide, we will generate refined molecules that block SAMHD1 tetramerisation and assess them in an in vitro dNTPase assay. In addition, we will also test two small molecule libraries in the same assay 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 evaluate the effect of the identified inhibitors on the innate immune response upon HIV-1 infection. Finally, we will analyze the impact of blocking SAMHD1 in DCs on the induction of antiviral immune response in vivo. Together, this project will identify inhibitors of the restriction factor SAMHD1 and evaluate the ability of these molecules to elicit an enhanced antiviral immune response upon HIV infection.
