Hepatitis C virus blocks interferon effector function by inducing protein kinase R phosphorylation

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Hepatitis C virus (HCV) infection induces antiviral interferon-stimulated genes (ISGs) but persists, indicating a mechanism to counteract host defenses.
• HCV utilizes an internal ribosome entry site (IRES) for translation of its polyprotein.

Purpose of the Study:

• To investigate how HCV evades the host's interferon-stimulated gene (ISG) antiviral response.
• To elucidate the role of RNA-dependent protein kinase (PKR) in HCV's evasion strategy.

Main Methods:

• Analyzing the effect of HCV infection on PKR activation and its impact on eukaryotic translation initiation factor eIF2 alpha phosphorylation.
• Assessing ISG mRNA and protein expression levels in HCV-infected cells with and without PKR suppression.
• Comparing host protein translation with HCV IRES-dependent translation under PKR activation.

Main Results:

• HCV infection activates PKR, leading to eIF2 alpha phosphorylation and reduced ISG protein synthesis despite normal ISG mRNA levels.
• Suppression of PKR in interferon-treated, HCV-infected cells restored ISG protein induction and enhanced interferon's antiviral efficacy.
• Activated PKR inhibited host protein translation, including ISGs, but did not affect HCV IRES-driven translation.

Conclusions:

• HCV activates PKR as a mechanism to suppress the translation of antiviral ISG proteins, thereby evading the host interferon response.
• This PKR activation paradoxically benefits HCV by selectively inhibiting host antiviral protein synthesis while allowing viral translation to proceed.