Cobalt chloride-mimicked hepatocyte cell hypoxia induces TREX1 leading to Hepatitis B virus restriction

Abstract

Background Restriction factors are host cell proteins that play a role in limiting virus replication. They form part of the intrinsic immune system and function as a first line of defense against viral infections. Hepatitis B virus (HBV) does not escape this rule and TREX1, a host restriction enzyme acts as an antiviral factor, leading to the inhibition of the virus. Methods TREX1-expressing constructs were generated and modified by site-directed mutagenesis. The location and activity of the different TREX1 constructs were analyzed by Immunofluorescence and FACS. HepaD38 cells were either transfected or transduced with the different TREX1 constructs in presence or absence of cobalt chloride-mimicked hypoxia and released HBV was quantified by qPCR. Results We identified TREX1 as a restriction factor that suppresses HBV replication. Furthermore, TREX1 expression was increased in the presence of cobalt chloride, a chemical agent mimicking hypoxia. Thus, by treating cells with cobalt chloride, TREX1 reduced HBV replication by a factor of 2, demonstrating that under hypoxic conditions, TREX1 restricts HBV replication. Finally, an analysis of 36 HBV-infected patients with hepatocellular carcinoma revealed that TREX1 expression was inversely correlated to the HBV viral and HBV cccDNA. Conclusion Current treatments are unable to eliminate HBV genomic reservoirs, which persist as covalently closed episomal circular DNA. TREX1 is a novel restriction factor that blocks HBV replication. It would be therapeutically relevant to study whether HBV nucleocapsid recycling containing TREX1 enzyme could be released into the nucleus and degrade the viral and nuclear DNA of infected cells.