We outline open questions regarding the biology of SAMHD1 whose answers will be important for understanding its function as a regulator of cell cycle progression, genomic integrity, and in autoimmunity.
Our results provide insights into the regulation of SAMHD1 activity, thereby facilitating the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.
SAMHD1 is a phosphohydrolase maintaining cellular dNTP homeostasis but also acts as a critical regulator in innate immune responses due to its antiviral activity and association with autoimmune disease, leading to aberrant activation of interferon.
In addition, we will discuss its role in autoimmunity and the antiviral immune response directed against HIV-1 and will evaluate the possibility of modulating SAMHD1 activity to generate an enhanced antiretroviral immune response.
SAMHD1 is a triphosphohydrolase enzyme that controls the intracellular level of deoxyribonucleoside triphosphates (dNTPs) and plays a role in innate immune sensing and autoimmune disease.
Mutations in SAMHD1 cause Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus.
Overall, these data suggest that SAMHD1 has a role in the nucleus that, if disrupted by mutation, leads to cytosolic accumulation of SAMHD1 and autoimmune disease.
Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease.