The interferon (IFN)-related cytokine interleukin (IL)-

The type III interferons (IFN-λ1, 2, 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.

Approximately 500 million people worldwide are chronically infected with the hepatitis B virus (HBV) or hepatitis C virus (HCV), and are therefore at an increased risk for developing fatal liver diseases such as cirrhosis and hepatocellular carcinoma. The intracellular antiviral responses induced by interferon (IFN)-a/-b and/or IFN-g play critical roles in the pathogenesis of HBV and HCV infection, and the function of IFN-k in the host immune response to these viruses is beginning to be revealed. A better understanding of how IFN-k influences HBV or HCV persistence is not only important for understanding the mechanisms of chronic virus infection, but also may lead to new approaches for improved antiviral therapies.

Chronic infection with hepatitis C virus (HCV) is associated with significant liver disease and is therefore an important public health problem. The current standard-of-care therapy for chronic HCV infection consists of a combination of pegylated (PEG) interferon (IFN)-α and ribavirin. Although this therapy effectively generates a sustained viral response in approximately half of treated individuals, it is associated with significant hematological and neurological side effects. A new family of IFN-related proteins (IFN-λ1, 2, and 3; or alternately, IL-29, 28A, 28B, respectively) possesses properties that may make these cytokines superior to PEG-IFN-α for HCV therapy. Genetic studies have also implicated these proteins in both the natural and therapy-induced resolution of HCV infection. This review summarizes the basic aspects of IFN-λ biology, the potential role of these cytokines in HCV infection, and the outlook for their therapeutic application.

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.