| Abstract: | Although few simian rotaviruses (RVs) have been isolated, such strains have been important for basic research and vaccine development. To explore the origins of simian RVs, the complete genome sequences of strains PTRV (G8P1]), RRV (G3P3]), and TUCH (G3P24]) were determined. These data allowed the genotype constellations of each virus to be determined and the phylogenetic relationships of the simian strains with each other and with nonsimian RVs to be elucidated. The results indicate that PTRV was likely transmitted from a bovine or other ruminant into pig-tailed macaques (its host of origin), since its genes have genotypes and encode outer-capsid proteins similar to those of bovine RVs. In contrast, most of the genes of rhesus-macaque strains, RRV and TUCH, have genotypes more typical of canine-feline RVs. However, the sequences of the canine and/or feline (canine/feline)-like genes of RRV and TUCH are only distantly related to those of modern canine/feline RVs, indicating that any potential transmission of a progenitor of these viruses from a canine/feline host to a simian host was not recent. The remaining genes of RRV and TUCH appear to have originated through reassortment with bovine, human, or other RV strains. Finally, comparison of PTRV, RRV, and TUCH genes with those of the vervet-monkey RV SA11-H96 (G3P2]) indicates that SA11-H96 shares little genetic similarity to other simian strains and likely has evolved independently. Collectively, our data indicate that simian RVs are of diverse ancestry with genome constellations that originated largely by interspecies transmission and reassortment with nonhuman animal RVs.Group A rotaviruses (RVs) are a major cause of acute dehydrating diarrhea in infants and children under the age of 5 years worldwide. These infections lead to approximately 527,000 deaths each year, the vast majority occurring in developing countries (33). RVs are also responsible for gastroenteritis in many other animal species, notably mammals and birds (16, 38). RVs are members of the family Reoviridae and possess a genome consisting of 11 segments of double-stranded RNA (dsRNA). The prototypic genome of a group A RV encodes six structural proteins (VP) and six nonstructural proteins (NSP) (5). The mature RV virion is a nonenveloped triple-layered icosahedral particle. The inner most protein layer is formed by the core lattice protein VP2. Attached to the interior surface of the VP2 layer near the fivefold axes are complexes of the viral RNA-dependent RNA polymerase VP1 and the RNA capping enzyme VP3. Collectively, VP1, VP2, VP3, and the dsRNA genome form the core of the virion (5, 11). The core is surrounded by VP6, the sole constituent of the intermediate protein layer of the virion. The antigenic properties of VP6 are used in classifying RV isolates into groups. The outer protein layer of the virion is composed of trimers of the VP7 glycoprotein penetrated by spikes of the VP4 attachment protein (50). The properties of VP7 and VP4 form the basis of a dual classification system defining RV G types (glycosylated) and P types (protease sensitive), respectively. At present, 23 G genotypes and 31 P genotypes have been recognized in the literature based on sequence analyses (17, 39, 42, 45, 47). Recently, a comprehensive sequence-based classification system was established for the RVs which, together with a uniform nomenclature, allows each genome segment of the virus to be assigned to a particular genotype. In the comprehensive classification system, the acronym Gx-Px]-Ix-Rx-Cx-Mx-Ax-Nx-Tx-Ex-Hx defines the genotypes of VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5 encoding genome segments (17, 18).Several years ago, Nakagomi et al. provided evidence by RNA-RNA hybridization assays that RVs originating from different animal species could be resolved into genogroups based upon the existence of unique species-specific genome constellations (29-31). More recently, the concept that RVs preferentially retain certain species-related genome constellations has been further supported by whole-genome sequencing (8, 24). For human RVs, two major genogroups (Wa-like genogroup 1 and DS-1-like genogroup 2) and one minor genogroup (AU-1-like genogroup 3) have been described (8, 17, 30). Although these genogroups are generally species specific, it is believed that the human AU-1 genogroup is of feline origin (31) and that the human Wa and DS-1 genogroups share common ancestor with porcine and bovine RVs, respectively (17). Another recent study based on full genome sequence data has indicated that the rarely seen human G3P3] RVs are of feline or canine origin (46). Two additional sequence-based studies have indicated that human RVs with P14] specificity may have originated after interspecies transmission from rabbit RVs and RVs from hosts belonging to the order Artiodactyla (i.e., hoofed mammals with even toes, including ruminants and pigs) (19, 20). These examples indicate that interspecies transmission of entire RV gene constellations from one host species to another may contribute significantly to viral evolution. In addition to interspecies transmission, complete genome sequencing of RVs have revealed multiple examples of naturally occurring inter- and intragenogroup reassortment (17, 19, 21-23, 37, 41).The simian RV strains, notably RRV and the SA11 derivatives (e.g., SA11-Cl3 and SA11-4F), have been used extensively as models in the study of all aspects of RV biology, including characterizing genome replication and virion assembly, delineating high-resolution structures of viral proteins and the virion capsid, and describing the functions of viral proteins. Moreover, the RRV strain was used to create a set of human-simian reassortant viruses that formed the basis of the first commercially licensed RV vaccine (Rotashield; Wyeth Laboratories) (10). Serological analyses have indicated that simian RVs are probably endemic in wild nonhuman primate (NHP) species in Africa (32). However, whether or not unique genogroups or preferred genome constellation exist for the simian RVs has not been determined, because of the lack of comprehensive genetic data. Most simian RVs isolated to date (e.g., rhesus macaque viruses RRV 43] and TUCH 25] and the pig-tailed macaque virus PTRV 9]) have been recovered from monkeys kept in captivity in the United States. An important exception is the SA11 isolate, which was recovered from a vervet monkey in South Africa (15). Simian RV infections occur mostly in young monkeys, similar to human RV infections in children (32, 40).To gain further insight into the origins and properties of simian RVs, we sequenced and contrasted the genomes of PTRV, RRV, and TUCH with other RVs, including SA11-H96 (G3P2]), the only previously fully sequenced simian RV (41). Our results reveal that these four simian RVs are of divergent ancestry and have evolved by combinations of interspecies transmission and reassortment with RVs naturally occurring in other animal species. Thus, the simian RVs do not possess a common genome constellation nor define a unique genogroup. Although frequently used as disease models, the simian RVs show limited genetic similarity with the human RVs (genogroups 1 and 2) responsible for most human disease. |
