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Hepatitis C virus receptor expression in normal and diseased liver tissue.


Reynolds*, G. M., H. J. Harris*, A. Jennings, K. Hu, J. Grove, P. F. Lalor, D. H. Adams, P. Balfe, S. G. Hubscher, and J. A. McKeating. Hepatology 47:418-27, 2008. (* - joint first authorship)

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This paper explores the localization of the 3 major HCV receptors in the human liver. We found CD81, SR-BI and CLDN1 to be expressed on hepatocytes, consistent with current models of the site of HCV replication (first image below). CLDN1 co-localized with CD81 on both basolateral and sinusoidal faces of hepatocytes in vivo. We found that purified Sinusoidal Endothelial Cells (SEC) and Biliary Endothelial Cells (BEC) were not infectable by HCV. Transduction of SEC to express SR-BI did not render them permissive. We were intrigued to find that CLDN1 expression was elevated in liver biopsies from HCV infected patients, This observation was also seen when we measured CLDN1 expression in an in vitro infection system (second image below).


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 apical-canalicular TJ region and at basolateral-sinusoidal hepatocyte surfaces in normal tissue and colocalized with CD81 at both sites. In contrast, CLDN1 appeared to colocalize with SR-BI at the basolateral-sinusoidal surface. CLDN1 expression was increased on basolateral hepatocyte membranes in HCV-infected and other chronically inflamed liver tissue compared with normal liver. In contrast, CLDN4 hepatocellular staining was comparable in normal and diseased liver tissue. HCV infection of Huh-7.5 hepatoma cells in vitro significantly increased CLDN1 expression levels, consistent with a direct modulation of CLDN1 by virus infection. In HCV infected livers, immunohistochemical studies revealed focal patterns of CLDN1 staining, suggesting localized areas of increased CLDN1 expression in vivo which may potentiate local viral spread within the liver.

Reynolds figure

Immunohistochemical staining of normal liver for HCV receptors. Normal liver tissue was stained with antibodies specific for (A) CD81, (B) SR-BI, (C) CLDN-1 and (D) non-immune serum control (x400 magnification). Positive staining is shown in red, arrows indicate: H–hepatocyte; S–sinusoidal endothelium and BD-bile ducts.

Reynolds figure

CLDN-1 expression in HCVcc infected Huh-7.5 cells. Confocal imaging of anti-CLDN-1 staining at 1.7µg/ml (A,B) and 0.16µg/ml (C,D) of uninfected and JFH infected Huh-7.5 cells at 72h post infection. Representative images of uninfected (A,C) and HCVcc infected Huh-7.5 (B,D) are shown, with infected cells staining positive for NS5A (red). (E) A representative linear profile of anti-CLDN-1 (0.16µg/ml) fluorescence intensity expressed as arbitrary fluorescence units (F). (F) The average plasma membrane (black) and intracellular (grey) anti-CLDN-1 fluorescent intensity for 20 cells was determined by linear profiling uninfected, NS5A+ and NS5A- cells within the infected population. The average fluorescent intensity for JFH infected NS5A+ cells was significantly increased relative to uninfected cells (p<0.0001, nonparametric Mann Whitney T test).

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