Inhibition of Type III Interferon Activity by Orthopoxvirus Immunomodulatory Proteins

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Abstract
The type III interferon (IFN) family elicits an antiviral response that is nearly identical to that evoked by IFN-α/β. However, these cytokines (known as IFN-λ1, 2, and 3) signal through a distinct receptor, and thus may be resistant to the evasion strategies used by some viruses to avoid the IFN-α/β response. Orthopoxviruses are highly resistant to IFN-α/β because they encode well-characterized immunomodulatory proteins that inhibit IFN activity. These include a secreted receptor (B18R) that neutralizes IFN-α/β, and a cytoplasmic protein (E3L) that blocks IFN-α/β effector functions in infected cells. We therefore determined the ability of these immunomodulators to abrogate the IFN-λ–induced antiviral response. We found that (i) vaccinia virus (VACV) replication is resistant to IFN-λ antiviral activity; (ii) neither VACV B18R nor the variola virus homolog B20R neutralizes IFN-λ; (iii) VACV E3L inhibits the IFN-λ–mediated antiviral response through a PKR-dependent pathway; (iv) VACV infection inhibits IFN-λR–mediated signal transduction and gene expression. These results demonstrate differential sensitivity of IFN-λ to multiple distinct evasion mechanisms employed by a single virus.

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