Pathogenetic Mechanisms of Hepatitis C Virus-Induced B-Cell Lymphomagenesis

Pathogenetic Mechanisms of Hepatitis C Virus-Induced B-Cell Lymphomagenesis Fabio Forghieri, Mario Luppi, Patrizia Barozzi, Rossana Maffei, Leonardo Potenza, Franco Narni, and Roberto Marasca Section of Hematology, Department of Oncology, Hematology, and Respiratory Diseases, University of Modena and Reggio Emilia, 41100 Modena, Italy Received 26 April 2012; Accepted 1 June 2012 Academic Editor: Jürg Schifferli Copyright © 2012 Fabio Forghieri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Hepatitis C virus (HCV) infection is probably the most common chronic viral infection and affects an estimated 180 million people worldwide, accounting for 3% of the global population. Although the liver is considered to be the primary target, extrahepatic manifestations are well recognized among patients with chronic HCV infection. Epidemiological studies have clearly demonstrated a correlation between chronic HCV infection and occurrence of B-cell non-Hodgkin's lymphomas (B-NHL). The clinical evidence that antiviral therapy has a significant role in the treatment at least of some HCV-associated lymphoproliferative disorders, especially indolent B-NHL, further supports the existence of an etiopathogenetic link. However, the mechanisms exploited by HCV to induce B-cell lymphoproliferation have so far not completely clarified. It is conceivable that different biological mechanisms, namely, chronic antigen stimulation, high-affinity interaction between HCV-E2 protein and its cellular receptors, direct HCV infection of B-cells, and “hit and run” transforming events, may be combined themselves and cooperate in a multifactorial model of HCV-associated lymphomagenesis. 1. Introduction Hepatitis C virus (HCV) is an enveloped positive, single-stranded RNA virus, belonging to the Flaviviridae family [1]. During its replicative cycle it goes through a negative-stranded RNA, but not DNA, intermediate, so that integration of HCV nucleic acid sequences into the host genome seems unlikely. The HCV genome encodes a single polyprotein precursor of approximately 3000 amino acids, which is proteolytically processed by viral and cellular proteases to produce structural (nucleocapsid, E1, and E2) and nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The HCV envelope proteins consist of two heavily glycosylated proteins, E1 and E2, which act as the ligands for cellular receptors [1, 2]. Human CD81 is the first identified necessary receptor for HCV cell entry, which can directly bind with HCV E2 protein [3, 4]. CD81 is a widely distributed cell-surface tetraspanin that participates in different molecular complexes on various cell types, including hepatocytes, B-lymphocytes, T-lymphocytes, and natural killer cells. It has been proposed that HCV exploits CD81 not only to invade hepatocytes but also to modulate the host immune responses [5]. Infection with HCV affects an estimated 180 million people, accounting for 3% of the global population [6, 7]. HCV is a well-recognized etiologic agent of chronic hepatitis. Although the natural history of HCV infection is highly variable, an estimated 15% to 30% of patients in whom chronic infection develops have progression to cirrhosis over the ensuing three decades, and these latter patients warrant surveillance for complications, including hepatocellular carcinoma (HCC), which develops in 1%–3% of such patients per year [6, 7]. Indeed, the risk of HCC in the HCV-infected population is 23–35 times higher than in noninfected healthy individuals [8, 9]. Although the liver is considered to be the primary target of HCV infection, extrahepatic manifestations, such as mixed cryoglobulinemia (MC), which is a systemic immune complex-mediated disorder characterized by B-cell proliferation that may evolve into overt B-cell non-Hodgkin’s lymphoma (B-NHL) in about 10%–20% of patients several years after diagnosis, are often recognized among patients with chronic HCV infection [10–12]. Moreover, epidemiological evidences strongly suggest a close link between chronic HCV infection and de novo B-NHL, not complicating the course of MC [13–16]. The possible pathogenetic mechanisms of HCV-induced B-cell lymphomagenesis are reviewed. 2. Epidemiologic Association of HCV and B-NHL Evans and Mueller proposed that either epidemiologic or virologic guidelines need to be fulfilled to support an etiologic role for a virus in a given human cancer [17]. Suggested epidemiologic guidelines included the following: (a) the geographic distribution of viral infection should coincide with that of the tumor; (b) the presence of viral markers should be higher in case subjects than in matched control subjects; (c) viral markers should precede the tumor, with a higher incidence of tumors in persons with the marker than in those without; (d) prevention of viral infection should decrease tumor incidence [17]. Suggested virologic guidelines included the following: (a) the virus should be able to transform human cells in vitro; (b) the viral genome should be demonstrated in tumor cells and not in normal cells; (c) the virus should be able to induce the tumor in an experimental animal [17]. As far as the association between HCV infection and occurrence of B-NHL is concerned, most of the epidemiologic guidelines for causality from Evans and Mueller are met. HCV is associated with certain B-NHL types, especially in geographic areas with HCV endemicity, like Italy, Japan, and Egypt, where prevalence rates range from 20% to 40% [14, 15, 18–21], whereas in nonendemic areas, as Northern Europe, North America and United Kingdom, the prevalence of HCV infection in B-NHL is far less than 5% [22–24]. The possibility is raised that in these latter geographic areas where HCV prevalence among subjects not affected with B-NHL is low, the spread of the virus may be recent, thus not allowing the full consequences on B-NHL development to be observed. Moreover, studies from areas with low HCV prevalence may not have included sufficient numbers of patients to detect a significant association between HCV and B-NHL [16]. Taken together, the epidemiologic analyses demonstrated that the prevalence of HCV infection in patients with B-NHL is approximately 15% [25]. The prevalence of anti-HCV antibodies and/or HCV RNA sequences is significantly higher in patients with B-NHL than in patients with other lymphoid malignancies or in age matched healthy subjects. Furthermore, HCV infection often precedes by years the occurrence of lymphomas [26]. In a recent meta-analysis focusing on 15 studies, the pooled relative risk (RR) of all B-NHL among HCV-positive persons was found to be 2.5 (95% confidence interval (CI), 2.1–3.1) in case-control studies and 2.0 (95% CI, 1.8–2.2) in cohort studies [27]. Another meta-analysis reviewed dat (...truncated)