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J Hepatol. 2011 Sep;55(3):536-544. doi: 10.1016/j.jhep.2010.12.021. Epub 2011 Jan 23.

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

Author information

1
Department of Gastroenterology, Alfred Hospital, Commercial Road, Prahran, 3181 Victoria, Australia. Electronic address: M.Berzsenyi@alfred.org.au.
2
Burnet Institute for Medical Research and Public Health, Commercial Road, Melbourne, 3004 Victoria, Australia.
3
Department of Pathology, Alfred Hospital, Commercial Road, Prahran, 3181 Victoria, Australia.
4
Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn St., North Melbourne, 3051 Victoria, Australia.
5
Neuroproteomics and Neurogenomics Platform and Centre for Neuroscience, University of Melbourne, Melbourne, 3010 Victoria, Australia.
6
Center for Cancer Biology, Hanson Institute and School of Molecular and Biomedical Science, The University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia.
7
Infectious Diseases Unit and Victorian HIV Service, Alfred Hospital, Macfarlane Burnet Institute for Medical Research and Public Health, Commercial Road, Melbourne, 3004 Victoria, Australia.
8
Department of Gastroenterology, Alfred Hospital, Commercial Road, Prahran, 3181 Victoria, Australia.

Abstract

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.

PMID:
21266183
DOI:
10.1016/j.jhep.2010.12.021
[Indexed for MEDLINE]

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