Mark D Berzsenyi1, David J Woollard2, Catriona A McLean3, Scott Preiss4, Victoria M Perreau5, Michael R Beard6, D Scott Bowden4, Benjamin C Cowie4, Shuo Li2, Anne M Mijch7, Stuart K Roberts8. 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.
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/HIVpatients. 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.
Authors: Adam L Bailey; Michael Lauck; Mariel Mohns; Eric J Peterson; Kerry Beheler; Kevin G Brunner; Kristin Crosno; Andres Mejia; James Mutschler; Matthew Gehrke; Justin Greene; Adam J Ericsen; Andrea Weiler; Gabrielle Lehrer-Brey; Thomas C Friedrich; Samuel D Sibley; Esper G Kallas; Saverio Capuano; Jeffrey Rogers; Tony L Goldberg; Heather A Simmons; David H O'Connor Journal: Sci Transl Med Date: 2015-09-16 Impact factor: 17.956