Interferon-λ in HCV Infection and Therapy

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

Differential infection of dendritic cell subsets by virus-based vaccine platforms

Abstract The use of virus-based vectors as vaccine platforms represents an attractive alternative to immunization with non-replicating antigens. However, the precise mechanism by which many virus-based vaccine vectors prime the immune response remains unknown. Specific dendritic cell (DC) subtypes play key roles in priming immune responses and controlling virus replication, but their functions in generating protective immunity following vaccination with viral vectors are not well understood. We hypothesized that highly immunogenic viral vectors based on alphaviruses and rhabdoviruses infect DCs and promote direct antigen presentation that leads to the efficient induction of antigen-specific T cells. We found that distinct DC subtypes are differentially infected with specific virus-based vaccine vectors, and display differences in activation following infection. Mouse bone marrow-derived DCs that are produced by GM-CSF stimulation and resemble moDCs rapidly succumbed to infection. In contrast, DCs that are produced by Flt3L stimulation and resemble cDCs and pDCs were efficiently infected but survived. DC activation following virus infection was more pronounced in the Flt3L-derived DCs, and showed distinctive requirements for further virus replication. Although Flt3L-derived DCs produced significant amounts of type I IFN when infected with the vaccine platforms, the mechanism of DC infection and activation was independent of type I IFN receptor signaling. These results highlight the differential survival and activation of specific DC subsets following infection with viral vaccine vectors, and indicate potentially unique roles of DC subtypes in activating the immune response following immunization.</jats:p

Protective and Pathological Properties of IL-22 in Liver Disease Implications for Viral Hepatitis

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection affect >500 million people worldwide and are significant causes of liver cirrhosis and hepatocellular carcinoma. The pathogenesis of HBV and HCV infection can vary widely with respect to the outcome of initial infection to self-resolving acute or chronic disease, the extent of viremia and liver inflammation during chronic infection, and the eventual development of liver cirrhosis and hepatocellular carcinoma. The host immune response is an important factor in the variable consequences of these infections, because the innate and adaptive intrahepatic antiviral responses are an intricate balance of immune effector cells and cytokines that control virus replication but can also cause liver damage. IL-22 is an important cytokine that plays a pleiotropic protective, but sometimes also pathological, role in several tissues/organs, including the liver. Therefore, IL-22 is likely to be an important factor in the pathogenesis and clinical outcome of HBV and HCV infection. However, the precise beneficial, and possible detrimental, effects of this cytokine may vary among different disease states that are associated with distinct inflammatory microenvironments. This review summarizes our understanding of the protective and pathological activities of IL-22, with an emphasis on the liver, and discusses the implications of these effects as they relate to viral hepatitis

Interferon-λ in the Immune Response to Hepatitis B Virus and Hepatitis C Virus

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)-α/-β and/or IFN-γ play critical roles in the pathogenesis of HBV and HCV infection, and the function of IFN-λ in the host immune response to these viruses is beginning to be revealed. A better understanding of how IFN-λ 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