title: Impact of single nucleotide polymorphisms in the essential HCV entry factor CD81 on HCV infectivity and neutralization.
abstract: End stage liver disease caused by chronic infection with the hepatitis C virus (HCV) is a leading indication for liver transplantation, yet outcomes are poor since the liver graft is rapidly re-infected by HCV. Antibodies against the essential HCV receptor CD81 have been shown to inhibit HCV cell entry in vitro and in vivo and may represent an attractive treatment option. However, several CD81 variants exist at low levels in human populations. We aimed to investigate to what extent these variants function as HCV receptors and would be amenable to therapeutic interventions with CD81 antibodies. We used lentiviral expression to introduce wildtype or variant CD81 in the CD81(low) Lunet N4 cell line. HCV replication cycle steps and neutralization by CD81 antibodies were then investigated using full length HCV reporter viruses (HCVcc) as well as HCV pseudoparticles (HCVpp). We found that all tested CD81 variants support cell entry by HCVpp and HCVcc with an efficiency similar to wildtype CD81. Other replication cycle steps, namely intracellular RNA replication and release of new particles, were also unaffected by the presence of CD81 variants. Importantly, four neutralizing antibodies directed against the CD81 LEL (5A6, JS81, 1D6 and 1.3.3.22) retained their ability to inhibit HCV infection when wildtype CD81 on target cells was replaced with any of the CD81 variants. These data indicate that CD81 variants that exist in the human population are fully functional as HCV receptors and their presence would not diminish the efficacy of therapeutic regimens that include CD81-antibodies.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Deest
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Institute for Molecular Biology, Medical School Hannover, Hannover, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Westhaus
authors.affiliation: Division of Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Steinmann
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Institute for Molecular Biology, Medical School Hannover, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: von Hahn
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany. Electronic address: ciesek.sandra@mh-hannover.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ciesek
mesh_terms: D057134:Antibodies, Neutralizing / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060225:Tetraspanin 28 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D000998:Antiviral Agents; C554798:CD81 protein, human; D011991:Receptors, Virus; D060225:Tetraspanin 28
keywords: CD81 antibodies; Entry; Hepatitis C virus; Single nucleotide polymorphism