**1. Introduction**

Hepatitis C virus (HCV) infection is a global health problem. Up to 85% of HCV-infected patients may develop long-term chronic hepatitis C (CHC), a disease state associated with serious clinical sequela, including liver cirrhosis, hepatic fibrosis, and hepatocellular carcinoma [1–4]. It has been estimated that up to 20% of CHC patients will develop hepatic cirrhosis over

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a 20–25-year period, and these individuals are at an increased risk for developing end-stage hepatic diseases or hepatocellular carcinoma [4]. Therefore, aggressive antiviral treatments to successfully induce viral remission constitute a major strategy for reducing the morbidity and mortality associated with CHC.

amino acid sequence similarity reaches 30–80%. They are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes [12, 13]. However, in most viral infections, plasmacytoid dendritic cells (pDCs) are probably the major source of these cytokines. In contrast, IFN type II (IFN-γ) is a single gene cytokine unrelated in structure to IFN-α/β, which is produced largely by macrophages, natural killer (NK) cells, and T lymphocytes [12].

A Critical Risk Factor for a Major Side Effect of Interferon-Alpha Therapy: Activated Indoleamine…

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The host response against HCV infection is first triggered when a pathogen-associated molecular pattern (PAMP), presented by an infecting virus, is recognized and engaged by specific PAMP receptors expressed on the host cells. This leads to the activation of signals that ultimately induce the expression of antiviral effector genes [14, 15] (**Figure 1**). For RNA viruses, protein, and nucleic acid products of infection or replication have been identified as viral PAMPs. These are engaged by specific toll-like receptors (TLRs) or nucleic acid-binding proteins that serve as PAMP receptors [15–17]. The viral RNA of HCV contains each of these PAMP signatures, and is adequate to trigger the host response when introduced into naïve cells [18, 19]. In hepatocytes, which is the target cell of HCV infection, independent pathways

**Figure 1.** The host innate response to HCV infection. Adapted from Ref. [14]. (1) HCV RNA binding to RIG-I or TLR3 results in the activation IRF-3. The dimer of phospho-IRF-3 translocates to the nucleus, interacts with transcription partners and binds to the cognate-DNA PRD in the promoter region of IRF-3 target genes. (2) IRF-3 activation leads to the induction of IFN-β production. (3) Secreted IFN-β from the infected cells binds to the IFN-α/β receptor, and results in activation of the JAK-STAT pathway. The ISGF3 complex translocates to the nucleus, where it binds to the ISRE on target genes to direct ISG expression. IRF-7 is one of the ISGs and it is activated after expression through viral PAMP signaling. (4) The IRF-7 dimer and heterodimer with IRF-3 binds to VRE in the promotor region of IFN-α genes resulting in the production of various IFN-α subtypes and establishing a positive-feedback loop for IFN amplification. It is the IFN-α

component of the host response that is exploited by the current IFN-based therapy for HCV infection [14].

**2.2. Immune response for HCV infection and IFN induction**

Immunotherapy with interferon-alpha (IFN-α) is commonly used to treat CHC and several types of malignancies owing to its antiviral, antiproliferative, and immunoregulatory effects [5]. In clinical trials, more than 50% of CHC patients treated with combination therapy using IFN-α and ribavirin achieved a sustained viral response, defined as undetectable HCV in the blood 6 months following the end of treatment [4]. Despite the efficacy of IFN-α in CHC treatment, IFN-α therapy causes serious side effects; early signs include somatic symptoms (anorexia, pain, insomnia, fever, and fatigue). Prolonged therapy causes neuropsychiatric symptoms including depressive states, anhedonia, anxiety, and cognitive impairment. In particular, depression is a serious and frequently occurring side effect of IFN-α therapy, and this leads to discontinuation of the therapy in up to 45% of patients [6, 7]. Therefore, in order to avoid the discontinuation of IFN-α therapy owing to depressive symptoms induced by the cytokine, it is important to identify the risk factor(s) leading to the associated depressive symptoms.

A number of findings suggest that the neuropsychiatric side effects observed during IFN-α therapy may be linked to aberrations in the tryptophan (TRP)-kynurenine (KYN) pathway [8, 9]. Clinical studies have found that IFN-α therapy reduces plasma TRP and serotonin (5-hydroxythrptamine; 5-HT) levels [8] and increases KYN levels in plasma and cerebrospinal fluid (CSF). In addition, the KYN/TRP ratio, an index of indoleamine 2,3-dioxygenase 1 (IDO1) activity, is increased in patients receiving IFN-α therapy [8].

IDO1 is an extrahepatic enzyme that catalyzes the conversion of TRP to KYN, which can produce many neuroactive metabolites such as 3-hydroxykynurenine (3-HK), kynurenic acid (KA), and quinolinic acid (QUIN). Intriguingly, QUIN levels in CSF have been found to correlate with the severity of depressive pathology [10], and post-mortem studies have shown increased microglia QUIN levels in the frontal cortex of severely depressed patients [11].

In the current chapter, we present the findings of our latest study, which demonstrates the association between IFN treatment and changes in the TRP-KYN pathway in the blood of HCV patients. To do so, we investigated the effect of chronic *Ifn* gene expression on depression-like behavior and levels of brain TRP-KYN metabolites in mice. Our results suggest the possibility for the prediction of onset risk of depression as a side effect in HCV patients.
