Hepatitis C virus receptor expression in normal and diseased liver tissue

Abstract

The principal site of hepatitis C virus (HCV) replication is the liver. HCV pseudoparticles infect human liver derived cell lines and this suggests that liver-specific receptors contribute to defining HCV hepatotropism. At least three host cell molecules have been reported to be important for HCV entry: the tetraspanin CD81, scavenger receptor class B member I (SR-BI), and the tight junction (TJ) protein Claudin 1 (CLDN1). Hepatocytes in liver tissue coexpress CD81, SR-BI, and CLDN1, consistent with their ability to support HCV entry. CLDN1 localized at the apicalcanalicular TJ region and at basolateral-sinusoidal hepatocyte surfaces in normal tissue and colocalized with CD81 at both sites. at risk of developing serious progressive liver disease, with HCV being the leading indication for liver transplantation. The principal site of HCV replication is the liver; however, the cell types targeted by the virus and the frequency of infected cells are poorly defined. 1,2 The selective association of a virus with a target cell is initially defined by interactions between the viral glycoproteins and specific cell surface molecules. Recent advances have allowed us to study the mechanism of HCV entry: firstly, the development of the retrovirus pseudoparticle system [hepatitis C virus pseudoparticle (HCVpp)], which measures glycoprotein-dependent particle entry, 3,4 and secondly, the ability of the JFH-1 strain of HCV to replicate and release infectious particles in cell culture [hepatitis C virus, cell culture produced (HCVcc)]. [5][6][7] The observation that HCVpp infects human liver-derived cell lines in vitro suggests that liver-specific receptors contribute to defining HCV tropism for the liver. Recent evidence suggests that at least three host cell molecules are important for HCV entry in vitro: the tetraspanin CD81, 4,7-9 the scavenger receptor class B member I (SR-BI), 9-12 and the tight junction (TJ) protein Claudin 1 (CLDN1). 13 HCV glycoproteins have been reported to interact with CD81 and SR-BI. 14 Mutagenesis and antibody blocking studies suggest that the first extracellular loop of CLDN1 interacts with HCV 13 ; however, the ex-

Clinical relevance of detectable hepatitis C virus RNA in the context of direct-acting antivirals

“…We appreciate the observations made by Harris et al regarding the differences in claudin-1 expression in human liver between the report by Reynolds et al 1 and our work. 2 The main objective of our study was to assess the potential changes in tight junction proteins claudin-1 and occludin following hepatitis C virus (HCV) graft infection.…”

“…Harrington et al discuss the clinical relevance of detectable, but not quantifiable, hepatitis C viral (HCV) RNA during treatment with the two recently approved direct-acting antivirals (DAAs), boceprevir and telaprevir. 1 The clinical trials used to assess the efficacy of these new DAAs were not designed to assess response-guided therapy using the less than lower limit of quantification [LLOQ] cutoff. However, a viremia below the LLOQ, but with detectable amounts of virus, clearly indicates that peripheral clearance has not occurred and, by implication, that replicating virus is still present in the liver.…”

“…An understanding of the decline in CIs surely makes the assessment of end-of-treatment detectable (but below the LLOQ) results as false positives too convenient an explanation. 1 These transient viremias may be somewhat inconvenient to explain, but perhaps our understanding of the natural history of HCV infection in the context of DAAs is insufficient to simply overlook the possibility that these transient viremias represent detectable and real virus.…”

“…The reduction in the sustained virological response (SVR) rate between those patients that have a viremia less than the LLOQ and those that have no detectable viremia clearly indicates that lack of peripheral suppression is still a good surrogate for persistence. No assay currently available detects HCV down to a level of 0.001 IU/mL, as outlined in Figure 1 of Harrington et al 1 We have assessed the decreasing confidence interval (CI) associated with HCV reverse-transcriptase polymerase chain reaction (RT-PCR) on a panel of characterized HCV genotype 1b samples (100, 37, 10, 3.7, 1, 0.37, and 0.04 IU/mL; AcroMetrix; Invitrogen, Carlsbad, CA). The test platform was the Roche AmpliPrep and TaqMan 48 (Roche Molecular Diagnostics, Pleasanton, CA).…”

Cellular models for the screening and development of anti-hepatitis C virus agents

“…This model of primary and highly differentiated human hepatocytes infected with HCVser is clearly the one that most closely mimics the physiological situation. In addition, primary human hepatocytes were also shown to be sensitive to HCVpp (Codran et al, 2006;Meertens et al, 2008;Regeard et al, 2008) and HCVcc (JFH1) infection Reynolds et al, 2008). Freshly isolated primary human hepatocytes have been recently used to evaluate comparatively the transcriptome profiling induced by core, NS3 and NS5A, or the HBV HBx protein as a control (via infection with adenovirus) (Budhu et al, 2007).…”