Abstract
The tight junction protein claudin-1 (CLDN1) is necessary for hepatitis C virus (HCV) entry into target cells. Recent studies have made disparate observations of the modulation of the expression of CLDN1 on cells following infection by HCV. In one study, the mean CLDN1 expression on cells exposed to HCV declined, whereas in another study HCV infected cells showed increased CLDN1 expression compared to uninfected cells. Consequently, the role of HCV in modulating CLDN1 expression, and hence the frequency of cellular superinfection, remains unclear. Here, we present a possible reconciliation of these disparate observations. We hypothesized that viral kinetics and not necessarily HCV-induced receptor modulation underlies these disparate observations. To test this hypothesis, we constructed a mathematical model of viral kinetics in vitro that mimicked the above experiments. Model predictions provided good fits to the observed evolution of the distribution of CLDN1 expression on cells following exposure to HCV. Cells with higher CLDN1 expression were preferentially infected and outgrown by cells with lower CLDN1 expression, resulting in a decline of the mean CLDN1 expression with time. At the same time, because the susceptibility of cells to infection increased with CLDN1 expression, infected cells tended to have higher CLDN1 expression on average than uninfected cells. Our study thus presents an explanation of the disparate observations of CLDN1 expression following HCV infection and points to the importance of considering viral kinetics in future studies of receptor expression on cells exposed to HCV.
Highlights
hepatitis C virus (HCV) entry into target cells is a multi-step process involving interactions of the viral envelope proteins E1 and E2 with several cell surface receptors, namely, scavenger receptor class B type I (SR-BI) [1], the tetraspanin CD81 [2,3], and the tight junction proteins claudin-1 (CLDN1) [4] and occludin [5]
Model formulation We considered in vitro experiments where a population of target cells, T, with a known distribution of the CLDN1 expression level was exposed to HCVcc virions, V
The block may be due to genetic bottlenecks associated with mitosis (Webster B, Wissing S, Herker E, Ott M, and Greene W, presented at the 18th International Symposium on Hepatitis C Virus and Related Viruses, Seattle, Washington, September 2011)
Summary
HCV entry into target cells is a multi-step process involving interactions of the viral envelope proteins E1 and E2 with several cell surface receptors, namely, scavenger receptor class B type I (SR-BI) [1], the tetraspanin CD81 [2,3], and the tight junction proteins claudin-1 (CLDN1) [4] and occludin [5] (reviewed in [6]). Recent studies suggest a role of the CD81- CLDN1 receptor complex in HCV entry [7,8,9]. The host cofactors epidermal growth factor receptor (EGFR) and ephrin receptor A2 (EphA2) mediate HCV entry through regulation of the CD81-CLDN1 association [12]. Modulation of the expression of CLDN1 on cells is expected to alter the susceptibility of cells to HCV infection
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