Abstract
Accumulated evidence implies that hepatitis C virus (HCV) infects not only the liver but also the immune system. A lymphocyte-specific CD5 molecule was recently identified as essential for infection of T cells with native, patient-derived HCV. To assess whether the proposed hepatocyte receptors may also contribute to HCV lymphotropism, expression of scavenger receptor-class B type 1 (SR-B1), claudin-1 (CLDN-1), claudin-6 (CLDN-6), occludin (OCLN), CD5 and CD81 was examined by real-time RT-PCR and the respective proteins quantified by immunoblotting in HCV-prone and resistant T cell lines, peripheral blood mononuclear cells (PBMC), primary T cells and their subsets, and compared to hepatoma Huh7.5 and HepG2 cells. SR-B1 protein was found in T and hepatoma cell lines but not in PBMC or primary T lymphocytes, CLDN-1 in HCV-resistant PM1 T cell line and hepatoma cells only, while CLDN-6 equally in the cells investigated. OCLN protein occurred in HCV-susceptible Molt4 and Jurkat T cells and its traces in primary T cells, but not in PBMC. CD5 was displayed by HCV-prone T cell lines, primary T cells and PBMC, but not by non-susceptible T and hepatoma cell lines, while CD81 in all cell types except HepG2. Knocking-down OCLN in virus-prone T cell line inhibited HCV infection, while de novo infection downregulated OCLN and CD81, and upregulated CD5 without modifying SR-B1 expression. Overall, while no association between SR-B1, CLDN-1 or CLDN-6 and the susceptibility to HCV was found, CD5 and CD81 expression coincided with virus lymphotropism and that of OCLN with permissiveness of T cell lines but unlikely primary T cells. This study narrowed the range of factors potentially utilized by HCV to infect T lymphocytes amongst those uncovered using laboratory HCV and Huh7.5 cells. Together with the demonstrated role for CD5 in HCV lymphotropism, the findings indicate that virus utilizes different molecules to enter hepatocytes and lymphocytes.
Highlights
Hepatitis C virus (HCV) is a positive single stranded RNA virus that occurs as a symptomatic chronic infection in more than 170 million people
As the results showed (Fig. 1), Molt4 and Jurkat T cells displayed HCV RNA positive strand at levels comparable to those detected in primary T lymphocytes and peripheral blood mononuclear cells (PBMC) (P = 0.6), while CEM cells where entirely nonreactive and PM1 cells only occasionally expressed the strand at a very low level (Fig. 1A)
Despite that HCV is a hepatotropic virus and infection of hepatocytes is responsible for manifestations of hepatitis C, substantial experimental and clinical evidence indicate that HCV
Summary
Hepatitis C virus (HCV) is a positive single stranded RNA virus that occurs as a symptomatic chronic infection in more than 170 million people. Efforts to establish a robust HCV culture system have succeeded by transfecting human hepatoma Huh cells with a full-length HCV genome derived from a Japanese patient with fulminant hepatitis C (JFH-1), resulting in secretion of infectious HCV JFH-1 particles (HCVcc) [6,7,8]. This infection model and other HCV surrogate systems, such as HCV pseudoparticles (HCVpp) [9,10], were applied to identify and/or to confirm molecules previously proposed to mediate HCV infection of hepatoma Huh cells and related cells lines which are expected to mimic normal human hepatocytes. It remains uncertain to what degree these models and the molecules identified reflect events occurring in in vivo infection of hepatocytes with native virus
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