Analysis of Variability in the GII.P4 RNA-Dependent RNA Polymerase Gene of Noroviruses

Over the past three decades, the majority of norovirus outbreaks and sporadic cases have been caused by strains of the GII.4 genotype. Notably, this period has seen a periodic change in the norovirus variants within the GII.4 genotype, with some variants acquiring epidemic distribution. Currently, six polymerase gene variants classified as P-type GII.P4 (GII.P4US95, GII.P4FarmingtonHills, GII.P4Hunter, GII.P4Yerseke, GII.P4DenHaag, and GII.P4NewOrleans) are represented in public nucleotide sequence databases, corresponding to GII.4 genotype variants of the gene encoding the main capsid protein VP1 of norovirus. In this study, the nucleotide sequence of the complete RdRp gene was obtained for a strain from Nizhny Novgorod, identified as GII.4Sydney[P4NewOrleans]. According to the results of Bayesian phylogenetic analysis based on RdRp GII.P4 gene sequences available in the GenBank database divided the analyzed strains into clusters according to polymerase variant. Within these clusters, lineages of intervariant recombinants are formed in accordance with the affiliation of the capsid protein variants associated with this polymerase variant. Analysis of the deduced amino acid sequences revealed substitutions specific to different polymerase variants that have emerged and become established within the norovirus population. It appears that the emergence of new norovirus variants within the GII.4 genotype involves selection for strains in which the polymerase and major capsid protein genes have coevolved, conferring certain advantages that facilitate further dissemination. These findings are highly relevant for advancing therapeutic strategies targeting RdRp inhibition for norovirus treatment and for development of specific prophylactic agents.