SAMHD1 Suppression of Antiviral Immune Responses

SAMHD1 is a host triphosphohydrolase that degrades intracellular deoxynucleoside triphosphates (dNTPs) to a lower level that restricts viral DNA synthesis, and thus prevents replication of diverse viruses in nondividing cells. Recent progress indicates that SAMHD1 negatively regulates antiviral innate immune responses and inflammation through interacting with various key proteins in immune signaling and DNA damage-repair pathways. SAMHD1 can also modulate antibody production in adaptive immune responses. In this review, we summarize how SAMHD1 regulates antiviral immune responses through distinct mechanisms, and discuss the implications of these new functions of SAMHD1. Furthermore, we propose important new questions and future directions that can advance functional and mechanistic studies of SAMHD1-mediated immune regulation during viral infections. SAMHD1 negatively modulates innate and adaptive immune responses to HIV-1 infection via the cGAS/STING pathway. SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by interacting with key proteins in the NF-κB and type I interferon pathways. The PI3K/AKT/IRF3 signaling pathway is important for type I interferon expression induced by SAMHD1-defeciency. SAMHD1 prevents interferon induction by promoting nascent DNA degradation during cellular DNA replication. SAMHD1 increases immunoglobulin hypermutation in activated B cells, thereby contributing to antibody diversity and antiviral immunity.