Role of Interferons in Chronic Hepatitis C Infection

Abstract

It is known that the production of and/or response to interferon (IFN) are deregulated during chronic hepatitis C virus (HCV) infection. In particular, several studies have shown that patients with chronic HCV infection who have a high natural level of IFN-stimulated genes (ISGs) do not achieve viral clearance and have a poor response to treatment with pegylated IFNα and ribavirin. The viral and/or host factors that are responsible for the higher endogenous ISGs expression in some HCV infected patients compared to others remain to be determined. However, type III IFNs, and in particular the new discovered IFN lambda (L) 4 Gene, appear to play a dominant role in driving ISGs response and in contributing to the establishment of HCV persistence. This review focuses on recent studies on how the ISGs response and the IFNλ genetic factors (interleukin-28B and IFNL4) affect the clinical outcome of HCV infection highlighting their impact in the current antiviral therapies with direct acting antiviral agents.

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

“…This apparently paradoxical action of IFN in HIV-1 infection is also wellestablished in chronic HCV infection where the majority of patients are unable to clear the virus and develop viral persistence in the face of a rapidly induced ISG response [3][4][5]. In parallel, when chronically HCV-infected patients with strong ISG expression were treated with IFNα and ribavirin, a virological response was very rare [3][4][5]. Moreover, when viral infections cannot be cleared, sustained type I IFN signaling seems to assume a predominantly immunosuppressive role, possibly to limit host toxicity and morbidity during persistent infection.…”

“…The IFN system consists of a broad family of cytokines that are key players in the development of both innate and adaptive immune responses. According to their cellular origin and the type of receptors they bind to, IFNs are grouped into three different types (Table 1) [5]. Type I IFN comprises multiple species, all of which signal through the same heterodimeric receptor [IFNA receptor (IFNAR)].…”

“…retroviral restriction factors). Moreover, both innate and adaptive immune cells respond to type I IFNs by enhancing antigen presentation and chemokine production, increasing antibody production by B cells and amplifying the effector function of T cells [5]. Unlike the multiple type I IFNs, type II IFN includes a single cytokine, IFNγ, mainly secreted by T lymphocytes and NK cells.…”

“…These functional similarities result from the activation of a common signaling pathway, although IFNλs engage a specific receptor complex composed of IFNLR1 (also known as IL-28RA) and the accessory chain IL-10R2. They have a more tissuerestricted expression than type I IFN, the liver tissues and epithelial cells being highly sensitive to their action [5].…”

“…Strikingly, and most distressingly for HIV-1infected patients, prolonged exposure to type I IFN in the chronic phase of infection is associated with desensitization and/or detrimental hyperimmune activation contributing to disease progression [1,2]. This apparently paradoxical action of IFN in HIV-1 infection is also wellestablished in chronic HCV infection where the majority of patients are unable to clear the virus and develop viral persistence in the face of a rapidly induced ISG response [3][4][5]. In parallel, when chronically HCV-infected patients with strong ISG expression were treated with IFNα and ribavirin, a virological response was very rare [3][4][5].…”