Porcine reproductive and respiratory syndrome virus antagonizes the host restriction factor SHFL to sustain viral programmed ribosomal frameshifting and replication

Porcine reproductive and respiratory syndrome virus (PRRSV) is a globally prevalent and economically devastating swine pathogen. Due to the high genetic diversity of PRRSV strains in the field, the current vaccination strategy cannot provide enough protection against PRRS threats. Programmed ribosomal frameshifting (PRF) is an essential mechanism in PRRSV that directs the synthesis of viral nonstructural proteins (nsps) and represents an attractive antiviral target. In this study, we conducted a comprehensive investigation into the antiviral effect of SHFL on PRRSV infection. Both canonical -1 PRF and the novel -2 PRF of PRRSV are suppressed by SHFL, demonstrating SHFL's broad-spectrum activity against different frameshifting mechanisms. We also found that PRRSV nsp12 and N counteract the expression of SHFL transcriptionally, thereby attenuating this host antiviral defense. Our study provides new insight into the antiviral mechanism of SHFL and the dynamic virus-host interaction, which may have implications for the development of PRRS control strategies.