Abstract
Counteracting innate immunity is essential for successful viral replication. Host cyclophilins (Cyps) have been implicated in viral evasion of host antiviral responses, although the mechanisms are still unclear. Here, we show that hepatitis C virus (HCV) co-opts the host protein CypA to aid evasion of antiviral responses dependent on the effector protein kinase R (PKR). Pharmacological inhibition of CypA rescues PKR from antagonism by HCV NS5A, leading to activation of an interferon regulatory factor-1 (IRF1)-driven cell intrinsic antiviral program that inhibits viral replication. These findings further the understanding of the complexity of Cyp-virus interactions, provide mechanistic insight into the remarkably broad antiviral spectrum of Cyp inhibitors, and uncover novel aspects of PKR activity and regulation. Collectively, our study identifies a novel antiviral mechanism that harnesses cellular antiviral immunity to suppress viral replication.
Highlights
Viruses encounter a remarkable array of intracellular antiviral defences that they must suppress or evade in order to replicate
Cyclophilin A (CypA) is an exciting target for broadly-acting antiviral intervention based on disrupting viral evasion and harnessing host intrinsic antiviral responses to combat infection
We found that CypA is crucial for hepatitis C virus (HCV) evasion of protein kinase R (PKR)-dependent, but not RIG-I-like receptors (RLRs)/MAVS-dependent, antiviral responses
Summary
Viruses encounter a remarkable array of intracellular antiviral defences that they must suppress or evade in order to replicate. The cyclophilin (Cyp) family of host proteins have emerged as key players at the virus-host interface. Cyclophilin A (CypA) is a cofactor for a variety of established and emerging viruses, including Flaviviridae such as hepatitis C virus (HCV) (Yang et al, 2008) and dengue virus (Qing et al, 2009), as well as Coronaviridae such as SARS coronavirus (Pfefferle et al, 2011). Like other Cyps, CypA has peptidyl prolyl isomerase activity, which is thought to induce conformational changes in bound target proteins (Wang and Heitman, 2005). Recruitment of CypA affects protein complex formation (Liu et al, 1991). The mechanisms by which CypA contributes to other viral infections are less well understood
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