Tuning a cellular lipid kinase activity adapts hepatitis C virus to replication in cell culture.
Nat Microbiol
; 2: 16247, 2016 12 19.
Article
em En
| MEDLINE
| ID: mdl-27991882
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.
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Base de dados:
MEDLINE
Idioma:
En
Revista:
Nat Microbiol
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Alemanha