Lambda and alpha interferons inhibit hepatitis B virus replication through a common molecular mechanism but with different in vivo activities

The type III interferons (IFN-λ1, 2, and 3) induce an antiviral response similar to IFN-α/β, but mediate their activity through a unique receptor. We found that like IFN-α/β, IFN-λ prevents the assembly of HBV capsids, demonstrating convergence of the two signaling pathways through a single antiviral mechanism. In contrast to IFN-λ, the structurally related cytokine interleukin (IL)-22 only minimally reduced HBV replication. The transcriptional program activated by IL-22 displayed little similarity to that induced by IFN-λ, but instead resembled the response elicited by IL-6. We also found that murine IFN-λ2 had only weak antiviral activity against HBV in the liver of transgenic mice, and that human IFN-λ2 activity in serum correlated with the sensitivity of the cytokine to proteases. These results demonstrate that the IFN-α/β and IFN-λ anti-HBV responses operate through a single molecular mechanism, and support the notion that IFN-λ plays a local, rather than systemic, role in antiviral immunity.