The objective of this project was to study the effect of PRRSV infection on interferon (IFN) signaling and determine the mechanism of the effect. Type I IFNs, such as IFN-α and -β, are critical to innate immunity against viruses and play important roles in the modulation of adaptive immunity. In this study, different PRRSV strains were compared for their effects in blocking the activity of type I IFNs, the PRRSV proteins were screened for their roles in the inhibition, and cellular proteins that PRRSV targets to dampen the host antiviral response were determined. We found that different PRRSV strains inhibit IFN-activated antiviral response at variable levels. Almost all strains tested inhibited the IFN signaling in MARC-145 cells, but two strains including MLV had much less effect in primary porcine alveolar macrophages (PAMs) than the other strains. Screening of the PRRSV structural and non-structural proteins identified several of them playing a role in the blocking of IFN signaling. A cellular protein, importin-α5 transporting proteins from cytoplasm into nucleus, was found to be the PRRSV target in inhibiting the IFN-mediated signal transduction. These results indicate that PRRSV has complex mechanisms in antagonizing the IFN-mediated antiviral response and different strains may use a whole or partial set of the means to accomplish the goal. This information will be helpful in designing new or improving current vaccines to combat PRRS. For further information, please contact Dr. Zhang at [email protected].