Human noroviruses (HuNoVs),N oroviruses (NoVs) are a group of positive-strand RNA viruses classified into the Norovirus genus in the Caliciviridae family. They are genetically divided into at least six genogroups associated with specific hosts: GI (human), GII (human), GIII (bovine), GIV (human and feline), GV (murine), and GVI (canine), which can be further divided into different genotypes. The prototype strain Norwalk virus (NV) represents genogroup I, genotype 1 (GI.1). NoVs that infect humans belong to genogroups GI, GII, and GIV, together referred to as human noroviruses (HuNoVs). HuNoVs are the leading cause of epidemic gastroenteritis worldwide, and illness can be particularly severe in infants, young children, and the elderly (1-4). Among HuNoVs, GII.4 noroviruses account for the majority of epidemic outbreaks of viral gastroenteritis, and new GII.4 variants emerge every 2 to 3 years replacing the previously dominant variants (5). Recent examples include the 2012-2013 winter outbreak of gastroenteritis caused by an emergent GII.4 variant, Sydney/2012 (6), and the rapid emergence of a fast-evolving GII.17 variant in late 2014 (7,8).Despite the disease burden of HuNoVs that documents the need for effective prevention and therapy strategies, currently there are no vaccines or antiviral drugs available to counter these viruses. This is largely due to the inability to efficiently propagate HuNoVs in cell culture and the lack of a simple small-animal infection model. Experimental infection studies in volunteers are currently the main strategy used to study antibody and serological