Interferon Alpha Induces Cellular Autophagy and Modulates Hepatitis B Virus Replication

Hepatitis B virus (HBV) infection causes acute and chronic liver diseases, including severe hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Interferon alpha 2a (IFN alpha-2a) is commonly used for treating chronic HBV infection. However, its efficacy remains relatively low. Yet, the immunological and molecular mechanisms for successful IFN alpha-2a treatment remain elusive. One issue is whether the application of increasing IFN alpha doses may modulate cellular processes and HBV replication in hepatic cells. In the present study, we focused on the interaction of IFN alpha signaling with other cellular signaling pathways and the consequence for HBV replication. The results showed that with the concentration of 6000 U/ml IFN alpha-2a treatment downregulated the activity of not only the Akt/mTOR signaling but also the AMPK signaling. Additionally, IFN alpha-2a treatment increased the formation of the autophagosomes by blocking autophagic degradation. Furthermore, IFN alpha-2a treatment inhibited the Akt/mTOR signaling and initiated autophagy under low and high glucose concentrations. In reverse, inhibition of autophagy using 3-methyladenine (3-MA) and glucose concentrations influenced the expression of IFN alpha-2a-induced ISG15 and IFITM1. Despite of ISGs induction, HBV replication and gene expression in HepG2.2.15 cells, a cell model with continuous HBV replication, were slightly increased at high doses of IFN alpha-2a. In conclusion, our study indicates that IFN alpha-2a treatment may interfere with multiple intracellular signaling pathways, facilitate autophagy initiation, and block autophagic degradation, thereby resulting in slightly enhanced HBV replication.

Automated summary

The study found that IFN alpha-2a treatment can interfere with multiple intracellular signaling pathways, promote autophagy initiation, but may also slightly increase HBV replication.