Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures

Abstract

Hepatitis C virus (HCV) is a blood-borne pathogen causing acute and chronic hepatitis. A significant number of people chronically infected with HCV develop cirrhosis and/or liver cancer. The pathophysiologic mechanisms of hepatocyte damage associated with chronic HCV infection are not fully understood yet, mainly due to the lack of an in vitro system able to recapitulate the stages of infection in vivo. Several studies underline that HCV virus replication depends on redox-sensitive cellular pathways; in addition, it is known that virus itself induces alterations of the cellular redox state. However, the exact interplay between HCV replication and oxidative stress has not been elucidated. In particular, the role of reduced glutathione (GSH) in HCV replication and infection is still not clear. We set up an in vitro system, based on low m.o.i. of Huh7.5 cell line with a HCV infectious clone (J6/JFH1), that reproduced the acute and persistent phases of HCV infection up to 76 days of culture. We demonstrated that the acute phase of HCV infection is characterized by the elevated levels of reactive oxygen species (ROS) associated in part with an increase of NADPH-oxidase transcripts and activity and a depletion of GSH accompanied by high rates of viral replication and apoptotic cell death. Conversely, the chronic phase is characterized by a reestablishment of reduced environment due to a decreased ROS production and increased GSH content in infected cells that might concur to the establishment of viral persistence. Treatment with the prooxidant auranofin of the persistently infected cultures induced the increase of viral RNA titer, suggesting that a prooxidant state could favor the reactivation of HCV viral replication that in turn caused cell damage and death. Our results suggest that targeting the redox-sensitive host-cells pathways essential for viral replication and/or persistence may represent a promising option for contrasting HCV infection.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…On the other hand, the chronic infection maintains a reduced environment to establish viral persistence. 291 Moreover, NOX-induced ROS play various roles in the mechanisms of oncogenesis by HCV, including genome instability, epigenetic regulation, inflammation and modulation of cell growth and death. 292 In RSV-infected airway epithelial cells, NOX-generated ROS trigger the activation of the transcription factors IRF and STAT, thereby inducing the expression of chemokines and cytokines involved in the immune/inflammatory responses of the lung.…”

Erratum to “Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures”

“…In the article titled “Counteraction of HCV-Induced Oxidative Stress Concurs to Establish Chronic Infection in Liver Cell Cultures” [1], there was an error in the Authors' Contributions section. Therefore, the section should be corrected as follows:…”

Oxidative stress, immunological and cellular hypoxia biomarkers in hepatitis C treatment-naïve and cirrhotic patients

“…Therefore, the redox homeostatic imbalance caused the pro-oxidant status and oxidative stress in our patients despite the increases in antioxidants. Reportedly, reactivation of HCV viral replication could favor the prooxidant state that exacerbates cell damage and death [26]. Lactate is produced in the peripheral tissues under normal physiological conditions, and is metabolized mainly in the liver and kidneys.…”