Down-regulation of intra-hepatic T-cell signaling associated with GB virus C in a HCV/HIV co-infected group with reduced liver disease

Background & Aims: Studies have shown that GB virus C (GBV-C) infection leads to reduced liver disease in hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infection. Considering that the underlying mechanism(s) are unknown, we aim to identify differential gene and protein expression associated with GBV-C in HCV/HIV co-infection that may be responsible for reduced liver disease. Methods: Liver, peripheral blood mononuclear cells (PBMCs), and plasma samples were collected from 43 HCV/HIV patients. Plasma was tested for GBV-C RNA by RT-PCR with NS5B gene primers. A microarray was performed on the liver and RT-qPCRs on the liver/PBMC samples. Hepatic protein expression was measured by immunohistochemistry. Results: Sixteen out of 43 patients had GBV-C RNA. GBV-C was associated with reduced hepatic fibrosis (p = 0.005) and inflammation (p = 0.007). The microarray analysis of the liver samples (n = 10) showed down-regulation of genes critical to intra-hepatic T-cell signaling associated with GBV-C. Quantitative RT-PCR of the liver samples (n = 13) confirmed the down-regulation of lymphocyte-specific protein tyrosine kinase (LCK) (p = 0.02) and docking protein 2 (DOK2) (p = 0.04). No differences in the expression levels of these genes were observed in PBMCs (n = 22) according to the GBV-C status. The hepatic expression of the LCK protein, measured by immunohistochemistry (n = 36), was decreased in CD3-positive T-cells within portal tracts associated with GBV-C (p = 0.003). This remained significant in multivariate analysis controlling for hepatic fibrosis and inflammation (p = 0.027). No differences were observed in plasma cytokine concentrations (n = 25) or ex-vivo peripheral T-cell responses (n = 13) versus GBV-C status. Conclusions: GBV-C infection is associated with down-regulation of critical genes involved in intra-hepatic T-cell signaling in HCV/HIV co-infection. This may be relevant to the pathogenesis of reduced HCV-related liver disease in HIV co-infection. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.