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Abstract: Protein kinase R (PKR), a sensor of double-stranded RNA, plays an important role in the host response to viral infection. Hepatitis C genotype 2a virus (HCV2a) has been shown to induce PKR activation to suppress the translation of antiviral interferon stimulated genes (ISGs), suggesting that PKR inhibitor can be beneficial for treating chronically HCV-infected patients in conjunction with interferon alpha and ribavirin. However, in this study, we found that PKR inhibition using siRNA PKR, shRNA PKR or PKR inhibitor enhanced HCV 1a replication and rendered Huh7.5.1 cells more susceptible to HCV1a infection. Additionally, PKR silencing suppressed NF-kB activation and NF-kB mediated STAT1 phosphorylation in Huh7.5.1 cells and HCV1a persistently infected Huh7.5.1 cells (2HDD4). These effects were accompanied by a reduction of interferon beta response and thereby enhanced HCV1a replication in Huh7.5.1 cells. We conclude that host cells can employ PKR activation to restrict HCV1a replication through regulation of NF-kB expression. [Copyright &y& Elsevier]

The recent progress in tumor immunology is a striking example of the successful application of modern biotechnology to understand the complex phenomenon of immune-mediated cancer rejection. Tumor antigens were identified and successfully utilized in active immunization trials to induce tumor antigen-specific T cells. This achievement has left, however, clinicians and researchers perplexed by the paradoxical observation that immunization-induced T cells can recognize tumor cells in standard assays but cannot induce tumor regression. A closer look at T cell physiology and tumor biology suggests that this observation is not so surprising. Here, we argue that successful immunization is one of several steps required for tumor clearance while more needs to be understood about how T cells localize and are effective within a tumor microenvironment impervious to the execution of their effector function. [Copyright &y& Elsevier]