A parapoxviral virion protein inhibits NF-κB signaling early in infection

Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor kappa B (NF-kappa B) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, we describe a NF-kappa B inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early in infected cells. Infection with ORFV073 gene deletion virus (OV-IA82.073) led to increased accumulation of NF-kappa B essential modulator (NEMO), marked phosphorylation of I kappa B kinase (IKK) subunits IKKa and IKK beta, I kappa B alpha and NF-kappa B subunit p65 (NF-kappa B-p65), and to early nuclear translocation of NF-kappa B-p65 in virus-infected cells (<= 30 min post infection). Expression of ORFV073 alone was sufficient to inhibit TNF alpha induced activation of the NF-kappa B signaling in uninfected cells. Consistent with observed inhibition of IKK complex activation, ORFV073 interacted with the regulatory subunit of the IKK complex NEMO. Infection of sheep with OV-IA82.073 led to virus attenuation, indicating that ORFV073 is a virulence determinant in the natural host. Notably, ORFV073 represents the first poxviral virion-associated NF-kappa B inhibitor described, highlighting the significance of viral inhibition of NF-kappa B signaling very early in infection.