Basic Sciences Division, Fred Hutchinson Cancer Research Center
Thursday 9:15-9:30, Ballroom A
Evolution of our immune systems is shaped by their interaction with pathogens. We asked whether adaptive changes in immune factors serve as “memories” of past viral infections and whether these can provide insights into ancient viruses. We also sought to determine whether virus-driven adaptive changes in host factors affect their ability to restrict modern-day viruses.
Host factor MAVS is a central component of the viral RNA sensing pathway. Not surprisingly, therefore, many viruses antagonize it. Such antagonism places selective pressure on MAVS to evolve away from being inhibited. Indeed, our phylogenetic analyses suggest that MAVS has recurrently and rapidly evolved in primates, consistent with the hypothesis that viral antagonism has shaped its evolution.
HCV is a modern-day virus that antagonizes MAVS. We sought to functionally determine whether adaptive evolution in MAVS has consequences for its ability to resist HCV antagonism. Indeed, we found that MAVS from multiple primate species have independently acquired adaptive changes at the same position that protect it from HCV antagonism.
In order to determine the nature of viral antagonists responsible for driving this evolution in MAVS, we functionally tested the ability of multiple HCV-like viruses from non-human primates to antagonize MAVS. Results from these experiments suggest that ancient hepaciviruses were likely responsible for driving MAVS evolution.
Thus, evolution of host immune factors can be used to gain insights into history of ancient viral infections. Our study also suggests that adaptations to ancient viruses likely have profound impact on host susceptibility to modern-day viruses such as HCV.
M.R.P. is supported by the Helen Hay Whitney Foundation. H.S.M. is a HHMI Early Career Scientist and is funded by NSF and NIH.