Key Points Noroviruses are a major cause of gastroenteritis, and there are currently no vaccines or antiviral treatments available to treat or prevent the >260 million gastroenteritis cases that are reported globally each year. Noroviruses have proven difficult to work with in the laboratory owing to the lack of cell culture systems and animal models, and therefore little is known about the pathogenesis caused by this virus, which has hampered the development of efficacious therapeutics. The norovirus family contains two genogroups (GI and GII) that are most commonly associated with enteric disease in humans, and these genogroups contain more than 25 different genotypes that account for most human norovirus cases. However, outbreaks caused by the GII.4 genotype occur much more frequently than those caused by other genotypes in the GII genogroup, and GI outbreaks occur even less frequently. Although the majority of norovirus outbreaks are caused by the GII.4 genotype, the molecular and biological factors that regulate this disease burden are only partially understood. The GII.4 genotype seems to operate in a similar fashion as influenza virus, whereby evolution of novel immune escape variants allows the virus to escape the predominant memory immune response. By contrast, the prototypic GI.1 noroviruses have remained relatively static over the same time period, evolving variants with identical histo-blood group antigen binding capabilities and similar antigenic properties. The molecular mechanisms governing differential evolution patterns remain a key mystery in the norovirus field. Immunity against noroviruses has been difficult to assess owing to the complex effects of host pre-exposure histories and differential host susceptibility, which is correlated with blood group and secretor status. However, recent work has suggested that the GI and GII genogroups may use different mechanisms to escape immunological memory and that this is perhaps directly related to the plasticity of and complex evolutionary-related sequence information encoded in the P2 subdomain of the capsid protein. The GII genogroup contains more amino acid sequence in the P2 subdomain, which may allow increased capsid plasticity and a tolerance for more amino acid variation or insertions and deletions. This would provide a larger repertoire of sequence targets for natural selection and adaptation to complex environmental selection processes, like herd immunity. By contrast, the GI genogroup contains less sequence information with more conserved, surface-exposed residues that are probably recognized by homologous antibodies as well as antibodies generated against heterologous GI strains. Thus, complex patterns of GI pre-exposure history, antibody cross reactivity and original antigenic sin may facilitate secondary infections of GI strains, whereas antigenic drift and receptor switching allow GII noroviruses, especially GII.4 viruses, to persist in human populations.
