Cellular stress responses in hepatitis C virus infection: Mastering a two-edged sword

Hepatitis C virus (HCV) infection affects chronically more than 150 million humans worldwide. Chronic HCV infection causes severe liver disease and hepatocellular carcinoma. While immune response-mediated events are major players in HCV pathogenesis, the impact that viral replication has on cellular homeostasis is increasingly recognized as a necessary contributor to pathological manifestations of HCV infection such as steatosis, insulin-resistance or liver cancer. In this review, we will briefly overview the different cellular stress pathways that are induced by hepatitis C virus infection, the response that the cell promotes to attempt regaining homeostasis or to induce dysfunctional cell death, and how the virus co-opts these response mechanisms to promote both viral replication and survival of the infected cell. We will review the role of unfolded protein and oxidative stress responses as well as the role of auto- and mitophagy in HCV infection. Finally, we will discuss the recent discovery of a cellular chaperone involved in stress responses, the sigma-1 receptor, as a cellular factor required at the onset of HCV infection and the potential molecular events underlying the proviral role of this cellular factor in HCV infection.