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 nsp1␣ replicase protein contributed to this property of PRRSV. Further mutagenesis analyses revealed that this function of nsp1␣ required the intact molecule, including the zinc finger domain, but not the cysteine protease activity. More importantly, we found that nsp1␣ 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 nsp1␣ in PRRSV infection. IMPORTANCE 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 nsp1␣, a critical viral factor involved in antagonizing host innate immunity. P orcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) is a positive-stranded RNA virus within the family Arteriviridae in the order Nidovirales (1) and represents a major threat to worldwide pork production. It is the major etiological agent for pig reproductive failure and respiratory distress in swine farms (2-4). The rapid evolution of this virus has led to the emergence of many virulent strains, exemplified by MN184 strains and Chinese highly pathogenic PRRSV (HP-PRRSV) (5, 6). The latter contributed to frequent, large-scale outbreaks of swine high-fever disease (atypical PRRS) that swept through China in 2006 to 2007, leaving Ͼ300 million pigs affected, with a high fatality rate ranging from 20% to 100%. HP-PRRSV has been plaguing the Chinese swine industry ever since (4, 6).The molecular mechanisms of PRRSV virulence and pathogenesis have remained unresolved, but it is clear that subversion of host immunity is a critical factor and that PRRSV has evolved strategies to escape host innate immune responses (7-10) and to modulate adaptive immunity, resulting in delayed, low-level induction of neutralizing antibodies (11-13) and cytotoxic T lymphocyte (CTL) responses (14-16). Deregulation of host immunity is thought to prevent the virus from clearance in an efficient and timely manner, leading to persistent infections in swineherds (17,18). Current studies have just...

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