Targeting Swine Leukocyte Antigen Class I Molecules for Proteasomal Degradation by the nsp1α Replicase Protein of the Chinese Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Strain JXwn06.

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is a critical pathogen of swine, and infections by this virus often result in delayed, low-level induction of cytotoxic T lymphocyte (CTL) responses in pigs. Here, we report that a Chinese highly pathogenic PRRSV strain possessed the ability to downregulate swine leukocyte antigen class I (SLA-I) molecules on the cell surface of porcine alveolar macrophages and target them for degradation in a manner that was dependent on the ubiquitin-proteasome system. Moreover, we found that the nsp1α replicase protein contributed to this property of PRRSV. Further mutagenesis analyses revealed that this function of nsp1α required the intact molecule, including the zinc finger domain, but not the cysteine protease activity. More importantly, we found that nsp1α was able to interact with both chains of SLA-I, a requirement that is commonly needed for many viral proteins to target their cellular substrates for proteasomal degradation. Together, our findings provide critical insights into the mechanisms of how PRRSV might evade cellular immunity and also add a new role for nsp1α in PRRSV infection. PRRSV infections often result in delayed, low-level induction of CTL responses in pigs. Deregulation of this immunity is thought to prevent the virus from clearance in an efficient and timely manner, contributing to persistent infections in swineherds. Our studies in this report provide critical insight into the mechanism of how PRRSV might evade CTL responses. In addition, our findings add a new role for nsp1α, a critical viral factor involved in antagonizing host innate immunity.