Moreover, other viruses of the herpes somehow family, such as EBV, have usurped the UPR to transcriptionally activate viral genes thereby controlling their lytic cycle [37]. What is the role of UPR in HCV infection? In this respect acute and chronic ER stress may play different and even opposite roles. For example, deletion of XBP-1 in the liver, which confers ER stress, impairs triglyceride synthesis and VLDL secretion [38]. Similar findings were found when GADD34, which neutralizes the PERK pathway of the UPR, was over-expressed in the liver [39]. In contrast, infliction of acute ER stress conditions by tunicamycin injection in various UPR deficient animals induced robust steatosis [40]. Interestingly, severe steatosis is also seen in HCV carriers particularly in genotypes II and III.

Taken together, the exact impact of UPR on liver lipid metabolism may be related to the level of UPR activation and its duration. Our data clearly show that in the course of productive HCV infection all 3 arms of the UPR pathways operate in tandem in a wave-like pattern, which coincides with the replication of JFH1 (Figure 1 and and2).2). This suggests that ER stress is proportional to the general load of viral proteins. Once replication declines, the cells regain homeostasis, and ER stress decreases but is not terminated (Figures 3 and and5).5). This feature has not been previously shown. Our results suggest that HCV, even at low levels of replication, constitutively activates the UPR. This may be due to cooperative activities of various HCV-encoded proteins with respect to their effect on ER physiology.

Indeed, the UPR was measured in response to over-expression of multiple HCV proteins such as the structural proteins E1 and E2, core as well as non-structural proteins [16]�C[20], [32]. The fact that we observed hyper eIF2�� phosphorylation at the chronic phase may actively serve the virus, as E1 and E2 HCV envelope proteins induce eIF2�� phosphorylation and repress global translation [17], while maintaining their synthesis in an eIF2�� independent fashion [41]. Other viral proteins, such as E2 and NS5A, negate eIF2�� phosphorylation [42], [43]. Thus the PERK Dacomitinib pathway of the UPR signaling is carefully regulated by the virus to allow optimal protein synthesis for its benefit. With respect to human pathology, chronic UPR activation may reflect the in vivo situation in HCV carriers. Direct evidence in humans for UPR induction are conflicting as a recent report demonstrates UPR activation in HCV patients long after the initial event of infection [44], while another study showed activation of the three UPR sensors but no induction of UPR-responsive genes [45].