title: Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture.
abstract: With a single exception, all isolates of hepatitis C virus (HCV) require adaptive mutations to replicate efficiently in cell culture. Here, we show that a major class of adaptive mutations regulates the activity of a cellular lipid kinase, phosphatidylinositol 4-kinase IIIα (PI4KA). HCV needs to stimulate PI4KA to create a permissive phosphatidylinositol 4-phosphate-enriched membrane microenvironment in the liver and in primary human hepatocytes (PHHs). In contrast, in Huh7 hepatoma cells, the virus must acquire loss-of-function mutations that prevent PI4KA overactivation. This adaptive mechanism is necessitated by increased PI4KA levels in Huh7 cells compared with PHHs, and is conserved across HCV genotypes. PI4KA-specific inhibitors promote replication of unadapted viral isolates and allow efficient replication of patient-derived virus in cell culture. In summary, this study has uncovered a long-sought mechanism of HCV cell-culture adaptation and demonstrates how a virus can adapt to changes in a cellular environment associated with tumorigenesis.
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Harak
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Meyrath
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Inés
authors.initials: I
authors.lastname: Romero-Brey
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schenk
authors.affiliation: INSERM U1183, Montpellier, France.|Department of Hepato-gastroenterology A, Hospital Saint Eloi, CHRU, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Gondeau
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Schult
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Esser-Nobis
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, USA.
authors.forename: Mohsan
authors.initials: M
authors.lastname: Saeed
authors.affiliation: Istituto Nazionale Genetica Molecolare (INGM) 'Romeo ed Enrica Invernizzi', Milan, Italy.
authors.forename: Petra
authors.initials: P
authors.lastname: Neddermann
authors.affiliation: Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Schnitzler
authors.affiliation: Internal Medicine, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain.
authors.forename: Sofia
authors.initials: S
authors.lastname: Perez-Del-Pulgar
authors.affiliation: Internal Medicine, University Hospital Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.affiliation: Internal Medicine, University Hospital Freiburg, Freiburg im Breisgau, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Gent, Belgium.
authors.forename: Philip
authors.initials: P
authors.lastname: Meuleman
authors.affiliation: Regenerative Medicine and Experimental Surgery (ReMediES), Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany.|German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Hannover, Germany.
authors.forename: Florian W R
authors.initials: FW
authors.lastname: Vondran
authors.affiliation: Istituto Nazionale Genetica Molecolare (INGM) 'Romeo ed Enrica Invernizzi', Milan, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Francesco
authors.affiliation: Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
authors.forename: Volker
authors.identifier: 0000-0001-8719-7608
authors.initials: V
authors.lastname: Lohmann