Rotavirus VP8*: Phylogeny, Host Range, and Interaction with Histo-Blood Group Antigens

The distal portion of rotavirus (RV) VP4 spike protein (VP8*) is implicated in binding to cellular receptors, thereby facilitating viral attachment and entry. While VP8* of some animal RVs engage sialic acid, human RVs often attach to and enter cells in a sialic acid-independent manner. A recent study demonstrated that the major human RVs (P4], P6], and P8]) recognize human histo-blood group antigens (HBGAs). In this study, we performed a phylogenetic analysis of RVs and showed further variations of RV interaction with HBGAs. On the basis of the VP8* sequences, RVs are grouped into five P genogroups (PI] to PV]), of which PI], PIV], and PV] mainly infect animals, PII] infects humans, and PIII] infects both animals and humans. The sialic acid-dependent RVs (P1], P2], P3], and P7]) form a subcluster within PI], while all three major P genotypes of human RVs (P4], P6], and P8]) are clustered in PII]. We then characterized three human RVs (P9], P14], and P25]) in PIII] and observed a new pattern of binding to the type A antigen which is distinct from that of the PII] RVs. The binding was demonstrated by hemagglutination and saliva binding assay using recombinant VP8* and native RVs. Homology modeling and mutagenesis study showed that the locations of the carbohydrate binding interfaces are shared with the sialic acid-dependent RVs, although different amino acids are involved. The PIII] VP8* proteins also bind the A antigens of the porcine and bovine mucins, suggesting the A antigen as a possible factor for cross-species transmission of RVs. Our study suggests that HBGAs play an important role in RV infection and evolution.