Molecular Signatures of Hepatitis C Virus (HCV)-Induced Type II Mixed Cryoglobulinemia (MCII)

Viruses 2012, 4, 2924-2944; doi:10.3390/v4112924 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Molecular Signatures of Hepatitis C Virus (HCV)-Induced Type II Mixed Cryoglobulinemia (MCII) Giuseppe Sautto *, Nicasio Mancini, Massimo Clementi and Roberto Burioni Microbiology and Virology Unit, “Vita-Salute” San Raffaele University, via Olgettina 58, Milan 20132, Italy; E-Mails: (N.M.); (M.C.); (R.B.) * Author to whom correspondence should be addressed; E-Mail: ; Tel.: +39-02-2643-5082; Fax: +39-02-2643-4288. Received: 1 October 2012; in revised form: 29 October 2012 / Accepted: 5 November 2012 / Published: 8 November 2012 Abstract: The role of hepatitis C virus (HCV) infection in the induction of type II mixed cryoglobulinemia (MCII) and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL), is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV) gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated. Keywords: hepatitis C virus (HCV); type II mixed cryoglobulinemia (MCII); B-cell nonHodgkin lymphoma (B-NHL); viral and host factors Viruses 2012, 4 2925 1. Introduction Hepatitis C virus (HCV) infection is a major public health problem with an estimated three to four million people infected each year worldwide and about 170 million carriers [1]. More than 350,000 people die annually from HCV-related liver disease, as current therapies are ineffective in a relevant percentage of cases, and also correlated with several side effects [1]. These estimates are even burdened by the extrahepatic aspects of HCV infection. In particular, about 60% of HCV-infected patients present cold-precipitable (cryoprecipitable) and noncryoprecipitable immune complexes that could be associated with the clinical onset of type II mixed cryoglobulinemia (MCII) [2]. This immune complex-mediated vasculitis is characterized by a primary B-cell clonal proliferation accompanied by the deposition of immune complexes composed of complement factors, mono/oligoclonal IgMs with rheumatoid factor (RF) activity bound to oligo/polyclonal IgGs that, in the case of HCV infection, are mostly directed against HCV proteins [3]. These data support a direct role of HCV in the pathogenesis of this lymphoproliferative disorder, together with the fact that 60%–80% of patients with MCII are infected with HCV and that effective anti-HCV treatment induces significant remissions of MCII [4]. However, not surprisingly, a reduction in MCII symptoms was shown also after anti-B-cell treatment (e.g. rituximab) suggesting a concomitant role of the pathogen and the host in the establishment of this autoimmune disorder [5]. It has been reported by several studies that about 10%–60% of HCV-infected patients presenting cryoglobulins are at risk of contracting symptomatic cryoglobulinemia, clinically characterized by association of purpura, weakness, and arthralgia, possibly complicated by severe renal and neurological involvement [5,6]. In more than 50% of these symptomatic patients, the clinical course is relatively benign with a good prognosis and survival rate [7]. However, it is not clear why some patients develop the above complications, even if several epidemiological risk factors have been identified, such as female gender (female/male ratio of about 2:1), advanced age, other associated autoimmune diseases, longer disease duration, or higher cryocrit levels [8–12]. Moreover, 5–10% of patients with cryoglobulinemic vasculitis will develop B-cell malignancies, especially B-cell nonHodgkin lymphoma (B-NHL), differently to the general HCV-infected population (0.2%–2.6%) [7,13]. It is actually accepted that HCV persistence contributes to oncogenesis by greatly favoring the biased proliferation of immunoglobulin (Ig)-secreting B-cells clones, which together with genetic and environmental factors may lead to mutational events that cause the onset of a malignant lymphoma [7,14–17]. In this review, we will analyze the host and viral factors that have been described to participate in HCV-induced MCII pathogenesis, in order to give an overview of the molecular mechanisms implicated (Figure 1). 2. HCV in Induction of MCII 2.1. HCV HCV is an enveloped, positive-stranded RNA virus belonging to the Hepacivirus genus of the Flaviviridae family, causing in the majority of cases (about 80%) a chronic infection [18]. On the basis Viruses 2012, 4 2926 of some conserved regions it can be divided in seven major genotypes and numerous subtypes, differently distributed in the world. In single infected patients, it circulates as a group of highly diversified viral variants, called quasispecies [19]. HCV genome is approximately 9,600 base pairs long and encodes a polyprotein precursor of about 3,000 amino acids. It is cleaved by viral and host proteases, resulting in a series of structural (core, E1 and E2) and nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B) [20]. Virions enter into the host cells, in particular hepatocytes, through a complex and finely regulated multistep process. In brief, the viral envelope type I membrane glycoproteins, E1 and E2 (HCV/E1-E2), allow clathrinmediated virus endocytosis interacting consecutively with several entry cellular cofactors such as glycosaminoglycans [21–23], low-density lipoprotein receptor [24,25], scavenger receptor class B type I [26], the tetraspanin CD81 [27], the tight-junction proteins claudin-1 and occludin, and the recently described Niemann-Pick C1-like 1 cholesterol absorption receptor [28–32]. As expected, the envelope glycoproteins, in particular HCV/E2, are the major targets of the humoral anti-HCV response and, therefore, the most hypervariable HCV proteins [33–35]. Recently, increasing data have been evidencing a very complex interplay among different regions of this protein and antibodies (Abs) endowed with highly diverging biological activity, suggesting “novel” mechanisms of HCV escape [36–39]. 2.2. HCV Infection and MCII Every HCV genotype have been found in infection-related MCII, even if different reports describe its higher prevalence among patients infected with HCV of genotype 1 and 2a/c [40–46]. The reported differences in the prevalence of HCV genotypes in different regions of the world could bias this observation, which should be therefore interpreted with caution. The mechanisms by which (...truncated)