Effector Genes of Interferon Action Against Hepatitis C Virus

Abstract

C urrent therapy of chronic hepatitis C virus (HCV) infection is based on type I interferon (IFN) preparations. 1 The IFNs comprise a class of related cytokines that induce antiviral and immunomodulatory actions of their target cells. 2,3 The type I IFNs include multiple IFN-␣ species and a single IFN-␤ species ( Fig. 1), and IFN-␥ is the single type II IFN. 3 The commercial IFN preparations that are largely used for HCV therapy consist of IFN-␣2a or IFN-␣2b subtypes. 4 The type I IFNs bind to a common receptor that is expressed on the surface of target cells. Receptor engagement leads to the activation of the Jak-STAT signaling pathway through the actions of the Jak1 and Tyk2 protein kinases, which catalyze phosphorylation events leading to the activation and heterodimerization of the signal transducer and activator of transcription (STAT) proteins STAT1 and STAT2. 2 STAT3 has also been shown to respond to type I IFN receptor signaling and is proposed to link IFN signaling events with cell growth regulation and the phosphatidylinositol 3-kinase pathway. 5,6 The STAT1/2 heterocomplex translocates to the cell nucleus, where it associates with p48/IRF-9 to form interferonstimulated gene factor 3 (ISGF3). 2 ISGF3 binds to the IFN-stimulated response element (ISRE) of cellular genes, known as IFN-stimulated genes (ISGs), leading to their induced expression and synthesis of the ISG products. Sequence motifs within the ISRE also serve as target sites for interferon regulatory factors (IRFs), whose actions and ISRE-binding properties contribute to define the overall spectrum and duration of ISG expression. 2,3 It is the biochemical actions of the ISG products that impart the primary therapeutic actions of IFN against HCV infection. However, IFN therapy continues to be problematic, because even under the best conditions, contemporary treatment protocols show limited efficacy such that only about one half of all treated patients exhibit sustained viral clearance. 1,4 The reasons for this limited efficacy are unclear, but are likely to involve both viral and host factors that ultimately affect the level and extent of ISG expression and function induced during the course of IFN therapy. [7][8][9][10] Results from microarray expression studies indicate that the human genome encodes hundreds, if not thousands of functionally diverse ISGs, some of which are known to direct antiviral actions. 11 However, the complete spectrum of ISGs has not been defined nor have the ISGs that impart control of HCV replication been identified. The refinement and further improvement of IFN therapy for chronic HCV infection will no doubt come from a better understanding of how IFN affects the infected hepatocyte and other target cells. This requires defining the spectrum and kinetics of ISG expression under in vivo conditions of IFN therapy and categorizing ISG expression patterns within patients who respond to therapy and in those patients who fail IFN therapy. In vivo studies that couple analyses of viral decay kinetics with microarray profili...

Sindbis Virus Translation Is Inhibited by a PKR/RNase L-Independent Effector Induced by Alpha/Beta Interferon Priming of Dendritic Cells

“…Thus, we hypothesized that IFN-␣/␤ can limit SB replication through PKR-dependent and PKR-independent mechanisms and that the alternative pathway requires IFN-␣/␤-mediated induction or activation of effector(s). Similar observations have been made for vesicular stomatitis virus (9,26), encephalomyocarditis virus (EMCV) (26,56), dengue virus (8), and hepatitis C virus (HCV) (12,29), and several alternative antiviral effectors have recently been described with activity against these viruses (9,21,24).…”

“…Constitutively expressed PKR and OAS/RNase L provide rapid cellular protection against many viral infections even before IFN-␣/␤ production, so that attempts to delineate activities of other effectors only became feasible with the derivation of PKR-and/or RNase-null mice (54,55). It has since become apparent that many viruses remain sensitive to the antiviral effects of IFN-␣/␤ even in the absence of PKR/RNase L, including EMCV (26), dengue virus (8), HCV (12,20,21,23,24,29,52), and SB (37).…”

“…p56 (product of GARG-16) severely inhibits initiation of cap-dependent translation at the level of eIF-3 ternary complex formation (20,21,23,24). Moreover, p56 directs PKR-independent suppression of HCV IRES translation during the IFN-␣/␤ response (12,21,23,24,52). However, induction of the GARG-16 gene was not consistently observed.…”

Robust hepatitis C virus infectionin vitro

“…Thus, HCV infection studies to date have involved infected patients (6)(7)(8) and chimpanzees (9)(10)(11)(12). The recent development of HCV replicon systems has also permitted the study of HCV translation and RNA replication in human hepatoma-derived Huh-7 cells in vitro (13,14), revealing some of the host-virus interactions that regulate these processes (15)(16)(17)(18)(19). Nonetheless, these replicons do not replicate efficiently without adaptive mutations (20,21), nor do they produce infectious virions.…”

Mitochondria as a Favourite Organelle for Invading Viruses

“…Obviously, viruses target the central parts of the proapoptotic signal transduction and execution machineries. Examples of proteins that subvert pro-apoptotic signals include viral proteins that block tumour necrosis factor (TNF) and its signals [69] viral proteins that inhibit ds-PKR, a protein kinase that is activated by ds-RNA (and which can initiate apoptosis in virus-infected cells) [70] viral proteins that inhibit p53 (a transcription factor that is often rate-limiting for DNA damageinduced apoptosis) [71,72] and viral proteins that inhibit caspase [73,74]. In addition, viral proteins are often acting on mitochondrial receptors and membranes to inhibit or induce MMP (Δψm) and this is the focus of the present paper (Tables 1 and 2).…”