TY - JOUR
T1 - Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture
AU - Harak, Christian
AU - Meyrath, Max
AU - Romero-Brey, Inés
AU - Schenk, Christian
AU - Gondeau, Claire
AU - Schult, Philipp
AU - Esser-Nobis, Katharina
AU - Saeed, Mohsan
AU - Neddermann, Petra
AU - Schnitzler, Paul
AU - Gotthardt, Daniel
AU - Perez-Del-Pulgar, Sofia
AU - Neumann-Haefelin, Christoph
AU - Thimme, Robert
AU - Meuleman, Philip
AU - Vondran, Florian W.R.
AU - Francesco, Raffaele De
AU - Rice, Charles M.
AU - Bartenschlager, Ralf
AU - Lohmann, Volker
N1 - Funding Information:
This project was funded by grants from the Deutsche Forschungsgemeinschaft (LO 1556/1-2, LO 1556/4-1 and TRR77, TPA1 to V.L., and TRR83, TP13 and TRR77, TPA1 to R.B.), as well as an HBIGS Postdoc stipend to C.H. This work was supported in part by the National Institutes of Health National Cancer Institute grant R01CA057973 and National Institute of Allergy and Infectious Diseases grants R01AI072613 and R01AI099284 (to C.M.R.) and by a Helmsley Postdoctoral Fellowship for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University (to M.S.).
Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2016/12/19
Y1 - 2016/12/19
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85006762169
U2 - 10.1038/nmicrobiol.2016.247
DO - 10.1038/nmicrobiol.2016.247
M3 - Article
AN - SCOPUS:85006762169
SN - 2058-5276
VL - 2
JO - Nature Microbiology
JF - Nature Microbiology
M1 - 16247
ER -