Primate lentiviral Vpx: insights into DNA sensing and zoonotic potential (360G-Wellcome-205236_Z_16_Z)

Innate detection of cytoplasmic DNA is central to human health and disease. DNA sensor cGAS and adaptor protein STING represent a key pathway. On recognition of viral cytoplasmic DNA, cGAS produces a secondary messenger that activates STING. This initiates signalling that stimulates transcription factors IRF3 and NF-kB and an inflammatory response. I have discovered that lentiviral accessory protein Vpx, expressed by zoonotic HIV-2 and related lentiviruses, is a DNA sensing antagonist. I have shown that Vpx selectively inhibits NF-kB, but not IRF3, activation downstream of cGAS/STING. I propose that Vpx is a tractable tool to interrogate the molecular mechanisms of DNA sensing that underpin diverse infectious and immune pathologies. Furthermore, Vpx allows examination of the central role for DNA sensing as a barrier to zoonosis. My specific objectives are: 1. To characterise the mechanism of Vpx inhibition of NF-kB activation. 2. To use SILAC to identify novel Vpx-host factor interactions occurring specifically after cGAS activation. 3. To characterise Vpx proteins from zoonotic and non-zoonotic simian lentiviruses, and epidemic and non-epidemic HIV-2, with a view to understanding the role of DNA sensing antagonism in cross-species lentiviral transmission. This fellowship will produce critical insight into central biological pathways of emerging medical importance.