Effect of the host genotype at a Porcine Reproductive and Respiratory Syndrome (PRRS) resistance marker on evolution of the modified-live PRRS vaccine virus in pigs

•Generated a host-genotype predictive model that does not correspond to phylogenetic analyses but predicts the correct host-genotype grouping based on PRRSV genotype.•Pigs with the unfavorable WUR allele (AA) had PRRS vaccine virus that was distinct and uniform as compared to the favorable genotypes (AB/BB).•Highest contributing consensus SNPs to the model were located in the PRRSV ORF1b, GP3/GP4, GP4, and M coding regions.•Subconsensus variant analysis indicated pigs with the AA allele had a limited subconsensus population as compared to AB/BB animals.Porcine Reproductive and Respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is one of the most economically impactful diseases to US and global swine producers. Protective efficacy of the primary means of PRRS control, i.e., modified-live virus (MLV) vaccines, is however, largely associated with genetically similar, or homologous, strains and to a much lesser extent with genetically dissimilar, or heterologous strains. The single nucleotide polymorphism (SNP) WUR10000125 on Sus scrofa chromosome 4 has been shown to account for 16% of the genetic variance in viral load and 11% of the genetic variance in weight gain in nursery pigs following PRRSV infection. In a previous study, pigs with either the favorable (AB and BB) or unfavorable (AA) genotype at this SNP were monitored for viral load by qRT-PCR on 7, 14, and 26 days post vaccination (dpv) with a ResPRRSV MLV. From this study, samples from 7 pigs were selected for PRRSV whole genome sequencing and bioinformatics analysis of consensus and subconsensus variants of the PRRSV. PRRSV consensus genomes were used to develop a host-genotype driven evolutionary model. Subconsensus variants were used to identify differential variant populations between host-associated PRRSV quasispecies. This resulted in a model that accurately predicted host WUR genotype from PRRSV consensus sequences and provided insight into the consensus-level changes that were associated with host-genotype at this SNP. The PRRSV consensus genomes carried by pigs with the AB/BB genotype were more variable (and vaccine-like) at 7 dpv compared to the PRRSV genomes carried by pigs with the AA genotype, which lacked any group-membership variability. These results suggest that the AB/BB genotype animals are more likely to develop a broader immune response than AA animals. Furthermore, subconsensus PRRSV population analysis revealed significant differences in vaccine quasispecies size be