Studying lentiviruses to understand mechanisms, regulation and consequences of nucleic acid sensing

I propose a new overarching hypothesis that innate immune sensing of nucleic acids, cell cycle regulation, and a hitherto unappreciated function of endogenous viral elements, contribute to an integrated system of regulating inflammatory responses to infection. Encouraged by preliminary data we will investigate the relationship between cell cycle and innate immune sensing by manipulating cell cycle and measuring responses to infection and relating expression of endogenous viral elements to cell cycle and their activation of nucleic acid sensing. We will also study the mechanisms of lentiviral Vpx/Vpr proteins taking molecular genetic and structural approaches to examine their enhancement of viral expression, manipulation of endogenous element expression and inhibition of innate immune signaling. We will also investigate the role of G3BP1 stress granules and their role in coordinating nucleic acid sensing with regulation of translation by PKR, mediated through cyclophilins. Overall our approach is to manipulate cellular pathways, for example cell division, and test sensing responses or manipulate virus and measure activation of sensing or viral inhibition of sensing. We expect to reveal mechanisms of nucleic acid sensing that can be tractably inhibited therapeutically and provide new mechanistic knowledge of inflammatory pathways broadly relevant to infectious and inflammatory diseases.