Around 50 chemokines have been described and are subdivided into four families according to the position of the two N-terminal cysteine residues: CXC, CC, XC and CX3C[15,16,17] (Table1). for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver. Keywords:Chemokines, Chemokine receptors, Hepatitis C virus, Viral hepatitis pathogenesis, Persistent infection, Viral escape mechanism == INTRODUCTION == The hepatitis C virus (HCV) is a hepatotropic non cytopathic virus very efficient in evading the host immune response. Hepatitis C infection is a major cause of chronic liver disease worldwide, affecting at least 170 000 000 people[1]. Approximately three quarters of infected subjects develop a chronic infection, but only one third progress to cirrhosis, hepatocellular carcinoma and liver failure without treatment[2]. Nowadays around 50% of patients treated with pegylated-interferon plus ribavirin clear the virus[3,4]. To control HCV infection an adequate specific T cell response is necessary[5-7], with T cells that are Amoxicillin Sodium able to migrate to the infected site to develop their effector functions (Figure1). Nevertheless, specific T cells fail to remove the virus in the majority of patients[7,8], because often a non-specific T cell population is recruited to the infection site, and these cells are presumably responsible for the chronic damage[9] (Figure2). == Figure 1. == Innate and adaptive immune response. Importance of specific cytotoxic T cell response. In a non-cytopathic viral infection the development of a vigorous specific cytotoxic T lymphocyte (CTL) response is essential. Professional antigen presenting Amoxicillin Sodium cells (APC) take up viral antigens and migrate from infected parenchyma to the lymph nodes to prime naive specific CTLs. These cells express the chemokine receptor CCR7 to reach the lymph nodes, attracted by CCL1 and CCL2 chemokines. After priming, Ntrk1 specific CTLs lose CCR7 expression and up-regulate CCR5 and CXCR3 chemokine receptors, then migrate to the Amoxicillin Sodium hepatic parenchyma to develop their effector function, attracted by the chemokines produced in the liver. During the early phase of infection, innate immunity is the first barrier for fighting against the virus. The cellular innate response is also recruited in the infected parenchyma by the interaction between chemokines and their receptors. == Figure 2. == Different migration potential between resolved and persistent HCV infection. In a resolved infection HCV-specific cytotoxic T lymphocytes (CTL) migrate rapidly to the infected liver, attracted by the chemokines produced by hepatocytes, succeeding in controlling HCV infection without liver damage. In persistent infection the migration of T cells to the liver may be impaired. High chemokine levels during infection may induce chemokine receptor down-regulation on T cells by molecule internalization. This mechanism could impair the migration of specific T cells during primary infection, which could inhibit HCV clearance. During the chronic phase, the persistent presence of HCV in the liver could keep a long-standing chemokine production, which could attract non-specific mononuclear cells to the liver, and be responsible for chronic liver damage. The relative migration impairment due to chemokine receptor down-regulation on non-specific T cells could modulate inflammatory infiltration of the liver, inducing chronic low-grade liver damage, which could favour host and virus long-term survival. In both scenarios the attraction of leukocytes to the liver is controlled by chemokines, which are chemotactic cytokines secreted by infected cells and interact with their receptors expressed on the recruited leukocytes[10] (Figure3). In an experimental model of influenza virus infection, the importance of appropriate chemotaxis to control viral infection was shown. In this model, cytotoxic specific CD8+ cells expressing inadequate chemokine receptors were not able to reach the infected site and clear the virus, while specific cytotoxic T cells expressing the correct chemokine receptors controlled the infection without tissue damage[11] (Figure4). On the other hand, it has also been demonstrated that chemokines and their receptors.