Chapter 12 - The Involvement of Tight Junction Protein Claudin-1 in Hepatitis C Virus Entry
Section snippets
Overview
Viruses exploit normal cellular processes to accomplish every step in their life cycle and these processes can differ in diverse cell types. Virus entry into a host cell is defined by specific interaction(s) with cell surface proteins or receptors that confer host and cellular tropism. Recent advances in the development of in vitro systems to study Hepatitis C virus (HCV) replication have demonstrated a role for tetraspanin CD81, scavenger receptor B I (SR-BI) and the tight junction proteins
Soluble HCV Glycoprotein E2
One of the first tools developed to study the interaction of HCV envelope proteins and cellular receptors was a soluble form of the envelope glycoprotein E2 (Selby, Glazer, Masiarz, & Houghton, 1994). sE2 protein can be produced in large quantities and was used as a surrogate model to study virus–cell surface interactions. It must be noted that HCV E1E2 glycoproteins exist as a heterodimer on the particle surface and sE2 association with host cell proteins may not recapitulate the true
HCV Pseudoparticles
To address the possible shortcomings of sE2 and to measure HCV glycoprotein-mediated entry events, we and others developed retroviral particles that incorporate HCV glycoproteins, termed HCV pseudoparticles (HCVpp) (Bartosch, Dubuisson & Cosset, 2003, Drummer et al., 2003, Hsu et al., 2003). Retrovirus particles bud from the plasma membrane and incorporate host cell or exogenous proteins into their envelope. HCVpp can be designed to express diverse glycoproteins (Lavillette et al., 2005,
The JFH-1 Strain of HCV
One of the key milestones in HCV research was the development of a HCV strain with the ability to replicate, assemble, and release infectious particles from cultured cells (HCVcc) in vitro (Lindenbach et al., 2005, Wakita et al., 2005, Zhong et al., 2006). This strain was cloned from a patient with fulminant hepatitis and is termed Japanese Fulminant Hepatitis-1 (JFH-1). JFH-1 particles are infectious for chimpanzees as well as for UpA-SCID chimeric mice, which contain transplanted human
Discovery of Receptors
All viruses must transverse the barrier of the cellular membrane and this is achieved by interaction with cell surface proteins or receptors that mediate viral binding and entry (Fig. 1). Virus–receptor interactions are highly specific and confer host and cellular tropism. HCV entry is a complex process involving a number of host factors, where initial adsorption of the virus may be facilitated by low affinity attachment factors like glycosaminoglycans (Barth et al., 2003), lectins (Lozach et
CD81
CD81 is member of the tetraspanin superfamily of type III transmembrane proteins that contain four transmembrane domains and conserved signature amino acid residues, including a conserved CCG motif and 4–6 cysteine residues that form critical disulfide bonds within the second large extracellular loop (LEL or EC2). Tetraspanins associate with a complex array of tetraspanin and nontetraspanin proteins at cholesterol-enriched microdomains and exert a diverse array of biological functions including
Scavenger Receptor Class B Type I
The initial evidence for a role of SR-BI in HCV entry came from the observation that HepG2 cells, which do not express CD81, bound HCV sE2, this was shown to be a specific interaction with SR-BI (Scarselli et al., 2002), a scavenger protein involved with lipoprotein metabolism. Lipoproteins comprise a cholesterol ester core surrounded by lipids and apoproteins. These structures transport triglycerides and cholesterol around the body and are categorized as high-density (HDL), low-density (LDL),
Claudins
Since many cell lines express CD81 and SR-BI and are nonpermissive for HCVpp entry (Bartosch, Dubuisson & Cosset, 2003, Hsu et al., 2003), other factors were predicted to be required for viral entry. A cDNA library derived from a permissive hepatocellular carcinoma cell line was cloned into nonpermissive 293 T cells, which express both CD81 and SR-BI. Permissive clones were identified to express Claudin-1 (Evans et al., 2007). Further work by Zheng et al. demonstrated that HCV could infect the
Occludin
Ectopic expression of CD81, SR-BI, and Claudin-1 in nonhuman cells failed to confer HCV entry. This led Ploss et al. (2009) to repeat the cDNA library screening process in the nonpermissive mouse cell line (NIH3T3) engineered to express human CD81, SR-BI, and Claudin-1. This led to the identification of Occludin as a fourth entry factor. The authors demonstrated that expression of Occludin in the nonpermissive renal carcinoma cell line, 786-O, or in TZM cells, a HeLa cell derivative, allowed
Tight Junction Proteins and Virus Entry
Tight junctions are responsible for the regulation of movement of solutes, ions, and water across endothelia or epithelia (Fig. 4). They also form a barrier preventing the access of pathogens to the underlying tissue (Guttman & Finlay, 2009, Krause et al., 2009, Van Itallie et al., 2008). Up to 30 proteins have been identified with distinct functions in maintaining barrier function of tight junctions (Shen et al., 2008). Several viruses have evolved to exploit tight junction proteins to enter
Effects of Cell Polarization on HCV Entry
Viruses that utilize tight junction proteins as part of their entry strategy mostly infect epithelial surfaces which show a simple planar polarity. These cells present apical and basal surfaces with their tight junctions located very close to the apical surface (Furuse & Tsukita, 2006, Guttman & Finlay, 2009). In contrast hepatocytes, the target of HCV, have a more complex polarity with at least two basal surfaces, the apical surface forming an enclosed channel or tube, the bile canaliculi (
Acknowledgments
We thank our lab colleagues and collaborators for helpful discussions over the years and acknowledge our funding from NIAID, MRC, and The Wellcome Trust.
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