My research vision involves using viruses as tools to understand the nature of molecular immunity and cell biology. Important scientific insights into innate immunity and cell metabolism have been gleaned by studying host proteins involved in HIV replication. Such proteins often have central cellular roles and are therefore relevant for physiological processes and pathogenesis of other diseases, including cancer.
I characterise host-pathogen interactions in retrovirus systems on a molecular and genetic level to further our knowledge of innate immunity and cell biology, and to provide novel therapeutic targets. I am focusing on one established, and one newly described, antiviral protein.
SAMHD1 is an interesting protein to understand the immune system and control of cell cycle. My collaborators and I were the first to show that the it degrades the building blocks of DNA, dNTP (Goldstone et al.) and in doing so prevents retroviral infection of quiescent cells. My work has demonstrated how regulation of its activity occurs (Groom et al. 2015). Others have since shown that SAMHD1 levels affect efficacy of certain cancer drugs (Herold et al. Nat Med 2017). However, little is known about the genetics behind variation in the general population, nor the potential consequences of its manipulation in vivo.
SAMHD1 and mitochondria
Non-physiological dNTP levels are known to cause mitochondrial pathologies. In my current fellowship I am understanding if manipulating SAMHD1 levels affects mitochondrial function, an important consideration for therapeutic interventions targeting this protein, and for understanding of intracellular metabolism.
Given SAMHD1’s position as a central protein in intracellular metabolism, innate immunity and cell cycle control, I wish to correlate SAMHD1 genotype variation in the general population with SAMHD1 expression and activity. I am currently analysing sequence variants from 12,000 individuals at 20 loci in collaboration with the Cambridge BioResource (CBR). I will characterise the effect of these variants on SAMHD1 expression and activity in vitro and in cells, with implications for the personalised therapeutics.