Hepatitis C virus infection in the immunocompromised host: a complex scenario with variable clinical impact

Anna Linda Zignego 0 1 Carlo Giannini 0 1 Laura Gragnani 0 1 Alessia Piluso 0 1 Elisa Fognani 0 1 0 Istituto Toscano Tumori (ITT) , Florence , Italy 1 Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Internal Medicine, University of Florence , Largo Brambilla 3, 50134 Florence , Italy The relationship between Hepatitis C Virus (HCV) infection and immunosuppression is complex and multifaceted. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This generally occurs during the immunosuppression state, and not at the reconstitution of the host response after immunosuppressive therapy discontinuation. The field of immunosuppression and HCV infection is complicated both by the different outcome observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. This review will briefly outline the current knowledge about the pathogenesis of both hepatic and extrahepatic HCV-related disorders and the principal available data concerning HCV infection in a condition of impairment of the immune system. Attention will be especially focused on some conditions - liver or kidney transplantation, the use of biologic drugs and cancer chemotherapy - for which more abundant and interesting data exist. - Introduction The relationship between Hepatitis C Virus (HCV) infection and immunosuppression, when compared with Hepatitis B Virus (HBV) infection, seems quite peculiar. This is possibly secondary to the differences - both in structure and replication mechanisms as well as in the natural history of infection - existing between the viruses. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This occurs during the immunosuppression state, and not at the reconstitution of the host response after therapy discontinuation. In fact, when we compare the average time and range of years necessary for the establishment of end-stage chronic liver disease (CLD) under normal conditions and in various categories of immunocompromised patients (i.e., transplanted patients, HIV-coinfected subjects, patients with hypogammaglobulinemia), a clear difference appears, with time intervals ranging from an average period of 30 years necessary to join the endstage CLD in normal conditions to an average interval of 2 years after liver transplantation (LT) [1] (Table 1). Overall, the varying behavior of the infection in different forms of immunosuppression outlines the important differences between the physiopathology of HCV- or HBV-related disorders, emphasizing the opportunities for different approaches and, not least, encouraging a Table 1 Time to develop liver cirrhosis in immunocompetent and immunosuppressed patients deeper analysis of pathogenetic mechanisms of virusrelated liver damage. The field of immunosuppression and HCV infection is complicated both by the different behavior observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. Of the great variety of situations leading to immunosuppression in the presence of HCV infection, the most numerous and interesting data derive from three conditions which are often interlinked: liver or kidney transplantation, the use of biologic drugs (monoclonal antibodies and interleukins with immunosuppressive activity) and cancer chemotherapy. The complex relationship between HCV and HIV has been previously deeply developed by others (for review see [15]) and it will not be the object of the present review. HCV: the burden of chronic infection and mechanisms of liver disease HCV infection is a critical public health problem There are about 200 million HCV carriers worldwide, more than 100,000 deaths every year are attributable to HCV and it is estimated that this number will significantly increase in the future [16]. HCV infection has a high propensity to persist in the host, in fact, acute infected patients fail to eradicate the virus in about 80% of cases and subsequently develop chronic infection. This condition leads to both extrahepatic and hepatic disorders, mainly chronic liver inflammation, cirrhosis and liver cancer [17]. To persist in the host, HCV uses different strategies aimed at subverting both the innate and adaptive immune responses. The immune system, in an attempt to clear the virus, induces continuous and extensive cytolytic activity on infected hepatocytes resulting in chronic inflammation, possibly evolving to severe liver disorders. The immune-mediated damage, although considered the main mechanism for HCV-related liver injury, is not exclusive, and a direct viral cytopathic effect has been suggested on the basis of experimental data (see below). Innate immunity Several lines of evidence indicate that the hepatocytolytic activity of the immune system is mainly mediated by the adaptive immunity (for review see [18]). However, components of the innate immunity, namely NK and NKT, can actively participate in the pathogenetic mechanisms by killing infected cell and, less directly, by the production of chemokines and cytokines with antiviral and proinflammatory activity as well as by shaping the adaptive immune response [19]. In HCV infection, a strong inhibition of NK cell response has been documented [20] and the mechanisms of this impairment could be related to the effects of E2 protein on the CD81 molecule in NK cells [21]. Adaptive immune response Concerning the adaptive immune response, it is well known that, in the acute phase of infection, a vigorous and multispecific T cell response is correlated with HCV clearance, whereas, in patients with chronic infection, the T cell response is generally delayed, transient and narrowly focused [22,23]. The dominant role of the adaptive immunity in determining the liver injury is confirmed by the detection of HCV-specific T lymphocytes in the peripheral blood or in the liver, several weeks after the infection and in coincidence with the peak of transaminase elevation, while no cytolytic activity is observed during the massive viral replication preceding this phase [24]. The (...truncated)