title: Phenotypic analysis of NS5A variant from liver transplant patient with increased cyclosporine susceptibility.
abstract: Hepatitis C virus (HCV) replication is limited by cyclophilin inhibitors but it remains unclear how viral genetic variations influence susceptibility to cyclosporine (cyclosporine A, CsA), a cyclophilin inhibitor. In this study HCV from liver transplant patients was sequenced before and after CsA exposure. Phenotypic analysis of NS5A sequence was performed by using HCV sub genomic replicon to determine CsA susceptibility. The data indicates an atypical proline at position 328 in NS5A causes increases CsA sensitivity both in the context of genotype 1a and 1b residues. Point mutants mimicking other naturally occurring residues at this position also increased (Ala) or decreased (Arg) replicon sensitivity to CsA relative to the typical threonine (genotype 1a) or serine (genotype 1b) at this position. This work has implications for treatment of HCV by cyclophilin inhibitors.
authors.affiliation: University of Wisconsin-Madison, Madison, WI 53726, United States.
authors.forename: Israr-Ul H
authors.initials: IU
authors.lastname: Ansari
authors.forename: Todd
authors.initials: T
authors.lastname: Allen
authors.forename: Andrew
authors.initials: A
authors.lastname: Berical
authors.forename: Peter G
authors.initials: PG
authors.lastname: Stock
authors.forename: Burc
authors.initials: B
authors.lastname: Barin
authors.forename: Rob
authors.initials: R
authors.lastname: Striker
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology* / Q000302:isolation & purification / Q000502:physiology; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D016031:Liver Transplantation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017354:Point Mutation; D011392:Proline / Q000235:genetics; D014180:Transplantation; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D016572:Cyclosporine; D011392:Proline; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase