Modulation of the type I interferon pathways by culture-adaptive hepatitis C virus core mutants

Hepatitis C virus (HCV) often establishes a persistent infection that leads to chronic liver diseases. The viral core protein modulates various cellular activities involved in this process. We found two mutations, K23E and V31A, in the core gene of the transfected HCV JFH-1 genome, which had been replicated for a prolonged period. The mutant viruses escaped immunochemical detection by a core-specific antibody and demonstrated enhanced RNA replication and protein expression, compared to the parental virus. The mutant core proteins bound less tightly than the parental type core to the DEAD-box RNA helicase DDX3 and attenuated the TBK1-mediated activation of interferon-related promoters. These results suggest a mechanism by which the viruses adapt to attenuate cellular antiviral activity and to establish persistent infection.Structured summary of protein interactionsDDX3 and COREcolocalize by fluorescence microscopy (View Interaction: 1, 2, 3) DDX3physically interacts with CORE by two hybrid (View Interaction: 1, 2, 3) COREphysically interacts with DDX3 by pull down (View Interaction: 1, 2, 3)

► We found culture-adaptive mutations in the core gene of Hepatitis C virus JFH-1 strain.
► The mutant viruses demonstrated enhanced RNA replication and protein expression.
► The mutant virus attenuated the TBK1-mediated activation of interferon-related promoters.
► The mutant core proteins bound less tightly than the parental type core to DDX3.
► Our results suggest a mechanism by which the viruses adapt to establish persistent infection.