Role of Porcine Reproductive and Respiratory Syndrome Virus Non-structural Protein 1 in Viral Replication and Pathogenesis

Porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine leads to a serious disease characterized by delayed and defective adaptive immune response. It is hypothesized that a suboptimal innate immune response is responsible for the disease pathogenesis. In the study presented here we tested this hypothesis and identified several non-structural proteins (nsps) with innate immune evasion properties encoded by the PRRS viral genome. Four out of the total 10 PRRSV nsps tested were found to have strong to moderate inhibitory effects on IFN-β promoter activation. The strongest inhibitory effect was exhibited by nsp1 followed by, nsp2, nsp11 and nsp4. We focused on nsp1α and nsp1β (self-cleavage products of nsp1 during virus infection) and nsp11, three of the nsps with strong inhibitory activity. All three proteins, when expressed stably in cell lines, strongly inhibited dsRNA signaling pathways. Nsp1β was found to inhibit both IRF3 and NF-κB dependent gene induction by dsRNA and Sendai virus. Mechanistically, the dsRNA-induced phopshorylation and nuclear translocation of IRF3 was strongly inhibited by nsp1β. Moreover, when tested in a porcine myelomonocytic cell line, nsp1β inhibited Sendai virus mediated activation of porcine IFN-β promoter activity. We propose that this nsp1β-mediated subversion of the host innate immune response plays an important role in PRRSV pathogenesis.