This hints at a potential heterogeneity of the inflammatory infiltrate and underscores the need for more detailed immunophenotypic analyses using markers specific for the major immune cell subsets, such as CD8, CD4, NK, and especially Treg. It is likely that different profiles of immune cell subpopulations may be better predictors of response outcome than merely the grade of the infiltrate taken as a whole, as suggested by ex vivo analyses.33, 34 Furthermore, ALT levels may be influenced by genetic and metabolic factors and thus they may not necessarily mirror the degree of the immune response. Paradoxically, our data show that the minor alleles of IL28B (i.e.,

rs8099917 G and rs12979860 T) can at the Akt inhibitor same time be unfavorable to the host, by reducing the chances of viral clearance, and favorable, by reducing the degree of liver inflammation and the rate of fibrosis progression in case of viral persistence. Studies showed that the minor alleles of IL28B were associated with reduced expression level of IL28B in peripheral blood mononuclear cells.9 IL28B induces strong adaptive immunity, blunting the Treg responses and stimulating CD8+ cytotoxic T-cell-mediated killing15 and increasing granzyme B expression and perforin release.16 The inflammatory infiltrate of chronic hepatitis C patients is mostly represented by CD8+ T cells,37-42 which

are supposed to play a major role in viral containment,39, 43 and Selleckchem BAY 73-4506 are also associated with the severity 上海皓元医药股份有限公司 of the inflammatory infiltrate.42, 43 Thus, IL28B alleles leading to increased

IL28B expression may partially revert the inhibition brought about on the HCV-specific CD8+ infiltrate by Tregs. Conversely, IL28B polymorphisms incapable of achieving spontaneous viral resolution would characterize an effector T-cell response that, even in the presence of a dysfunctional and/or exhausted virus-specific response, would be associated with persistent liver damage. This is only one hypothesis, because the effector functions of activated T cells are multifaceted, and may even include cytoprotective effects mediated by IL-22.44 Thus, the definitive immunopathogenetic interpretation of our results can only rely on a thorough phenotypic and/or functional analysis of the T-cell infiltrate. Our data did not show an association between IL28B polymorphisms and the occurrence of HCC among chronically HCV-infected patients, but the number of patients with HCC was likely insufficient to detect a significant effect, especially as the majority of patients with HCC were infected with HCV genotype 1. Other investigators found that the poor treatment response rs12979860 T allele was associated with HCC in a heterogeneous group of 412 patients with endstage liver cirrhosis due to mixed viral and nonviral etiologies.45 However, the study design did not allow for a specific analysis of the role of IL28B SNPs on the risk of developing HCC among HCV-infected patients.