title: Distinct CD55 Isoform Synthesis and Inhibition of Complement-Dependent Cytolysis by Hepatitis C Virus.
abstract: CD55/DAF, one of the regulators of complement activation, is known to limit excess complement activation on the host cell surface by accelerating the decay of C3 convertase. We reported previously that hepatitis C virus (HCV) infection or virus core protein expression upregulates CD55 expression. CD55 associates with HCV particles, potentially protecting HCV from lysis in circulation. An increase in CD55 on the surface of HCV-infected cells may inhibit complement-mediated cell killing. In this study, we show that Abs against cancer cell surface proteins induce complement-dependent cytolysis or Ab-dependent cell-mediated cytotoxicity of immortalized human hepatocytes in the presence of CD55-blocking Ab. CD55 has a secreted isoform (sCD55) that is generated by alternative splicing. We observed that sCD55 is induced in HCV-infected or HCV replicon-harboring cells, as well as in liver biopsy samples from chronically HCV-infected patients. Conditioned medium from HCV-infected hepatoma cells (Huh7.5 cells) or immortalized human hepatocytes inhibited C3 convertase activity and complement-dependent cytolysis of sheep blood erythrocytes. Chronically HCV-infected patient sera inhibited C3 convertase activity, further implicating HCV-specific impairment of complement function in infected humans. CD55-blocking Ab inhibited erythrocyte lysis by conditioned medium, suggesting that CD55/sCD55 impairs convertase activity. Together, our data show that HCV infection induces sCD55 expression in HCV-infected cell culture-conditioned medium and inhibits C3 convertase activity. This may have implications for modulating complement-mediated immune function in the microenvironment and on HCV-harboring cells.
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and.
authors.forename: Young-Chan
authors.initials: YC
authors.lastname: Kwon
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and.
authors.forename: Hangeun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and.
authors.forename: Keith
authors.initials: K
authors.lastname: Meyer
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and.
authors.forename: Adrian M
authors.identifier: 0000-0002-6075-9305
authors.initials: AM
authors.lastname: Di Bisceglie
authors.affiliation: Department of Internal Medicine, Saint Louis University, St. Louis, MO 63104; and Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO 63140 rayr@slu.edu.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Ray
mesh_terms: D018958:CD55 Antigens / Q000276:immunology / Q000378:metabolism*; D003167:Complement Activation / Q000502:physiology*; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016174:Hepacivirus; D006526:Hepatitis C / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms
chemical_list: D018958:CD55 Antigens; D017077:Culture Media, Conditioned; D020033:Protein Isoforms; D050577:Complement C3-C5 Convertases