Noroviruses, an important cause of acute gastroenteritis in humans, have been found to recognize the histo-blood group antigens (HBGAs) as receptors. Different noroviruses revealed different receptor-binding profiles associated with the ABO, secretor, and Lewis HBGA types. Direct evidence of HBGA receptor recognition in viral infection and tropism was obtained from human volunteer challenge studies on the prototype Norwalk virus, in which the infection rates of the volunteers matched well with the HBGA-binding profiles of the challenge virus , . Similar evidence was also obtained from investigation of outbreaks of gastroenteritis related to other genotypes of noroviruses , , although conflicting results also were reported. The HBGA-binding interfaces have been identified in the protruding (P) domain of the viral capsid protein, in which a group of scatted amino acids forms a conformational pocket on the distal surface of the viral capsid that interacts with individual oligosaccharide residues of the HBGA receptors – (Figure 1). These data indicate that the P domain is the primary site of receptor interaction, which plays an essential role in norovirus infection.
The crystal structures of the HBGA-binding interfaces of Norwalk virus (GI.1) and VA387 (GII.4) have been elucidated, each representing one of the two major genogroups of human noroviruses –. The receptor-binding interfaces of the two strains differ significantly in their structures, precise locations, receptor-binding modes, and amino acid compositions, although both locate on the top of the arch-like P dimer of the viral capsids . However, sequence alignment showed that the key residues responsible for HBGA binding are highly conserved among strains within but not between the two genogroups, while the remaining sequences of the P2 subdomain are highly variable  (Figure 1). These data indicate that HBGAs play an important role in norovirus evolution, although other factors, such as host immunity, may also be involved. Each of the two genogroups represents an evolutionary lineage characterized by distinct genetic traits. Strains within each lineage have further diverged into sub-lineages (genotypes), probably by functional selection or adaptation through structural constraints of the human HBGAs. The polymorphic human HBGAs are most likely the driving force of the divergence of human noroviruses.