Characterisation of innate immune DNA sensing and viral evasion strategies (360G-Wellcome-108183_Z_15_A)

We have identified an entirely new mechanism by which retroviruses regulate the process of DNA synthesis. We have discovered that, contrary to textbooks, the process of HIV-1 DNA synthesis occurs inside intact capsids and that the nucleotide fuel for DNA synthesis is sucked through regulated electrostatic channels formed by the hexmaeric capsid lattice making up the viral core. We have also discovered that the channels can open and close through a molecular iris formed by the capsid beta hairpin sequences at the 6-fold access of symmetry. This work is in press in Nature. Preliminary data suggest that non-pandemic forms of HIV do not properly regulate their capsid pores and that this causes these viruses to be less able to evade intracellular innate sensing mechanisms. This may explain their failure to reach pandemic levels of human-to-human transmission. Our current work aims to understand the molecular details of how pandemic HIV-1 regulates DNA synthesis through cofactor recruitment and regulation of the capsid channels. We also aim to understand whether the non-pandemic viruses also do this and to understand what features they lack. We also aim to understand when the process of channel regulation evolved, ie in the parental chimpanzee viruses or in humans as HIV-1.