Journal
NATURE MICROBIOLOGY
Volume 2, Issue 3, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nmicrobiol.2016.247
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Funding
- Deutsche Forschungsgemeinschaft [LO 1556/1-2, LO 1556/4-1, TRR77, TPA1]
- HBIGS Postdoc stipend
- National Institutes of Health National Cancer Institute [R01CA057973]
- National Institute of Allergy and Infectious Diseases [R01AI072613, R01AI099284]
- Helmsley Postdoctoral Fellowship for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University
- Greenberg Medical Research Institute
- Starr Foundation,
- Ronald A. Shellow
- M.D. Memorial Fund
- [TRR83]
- [TP13]
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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 IIIa (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.
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