Understanding the Role of Norovirus VP1 in Viral Infectivity and Persistence

Abstract

Human noroviruses (HNV) are a prevalent cause of gastroenteritis that contribute to >200,000 deaths each year and cost >£40 billion worldwide per annum. There is currently no approved vaccine or therapy, and a greater understanding of the virus life-cycle could help develop new approaches towards disease control. Although HNV infection is usually self-limiting, persistent infections can establish in immunocompromised people - however the underlying mechanisms are poorly understood. Our studies use the murine norovirus (MNV) model system to investigate fundamental virus biology, and several strains of MNV can also persist in the murine host. The primary receptor for MNV, CD300lf, interacts with a network of amino acids (AAs) on the protruding domain of the virus major capsid protein (VP1). We hypothesised that genetic variations leading to changes within this network of AAs could influence the VP1-CD300lf interaction and viral persistence. Bioinformatic analysis of the VP1-receptor interface highlighted variation in just a single AA that correlates with persistent MNV strains. To confirm this AA is important for receptor interactions we conducted in vitro evolution experiments on suspension or adherent grown cells. Passage through suspension cells resulted in the selection of hydrophobic residues at this position co-incidental with a 1.5-fold increase in viral titre. In contrast, small polar residues were maintained at this position during passage on adherent cells. Furthermore, infectivity assays with infectious clones suggest that hydrophobic residues favour infection of suspension cells over adherent cells. Work is ongoing to understand the importance of this AA on viral infectivity and persistence.