Cobalt Chloride-Mimicked Hepatocyte Cell Hypoxia Induces TREX1, Leading to Hepatitis B Virus Restriction

Restriction factors are host cell proteins that limit virus replication and form part of the intrinsic immune response, acting as a first line of defense. Hepatitis B virus (HBV) does not escape this rule and TREX1, a host restriction enzyme, plays a key role in inhibiting HBV replication.

TREX1-expressing constructs were generated and modified by site-directed mutagenesis. The location and activity of these constructs were analyzed by immunofluorescence and fluorescence-activated cell sorting. HepaD38 cells were transfected or transduced with TREX1 constructs with or without cobalt chloride-mimicked hypoxia and HBV replication was quantified by quantitative polymerase chain reaction.

TREX1 was identified as a restriction factor that suppresses HBV replication. Furthermore, TREX1 expression was enhanced under cobalt chloride-induced hypoxia, leading to a 2-fold reduction in HBV replication. Analysis of 36 HBV-infected patients with hepatocellular carcinoma revealed that TREX1 expression was inversely correlated to the HBV viral load and HBV covalently closed episomal circular DNA (cccDNA).

Current treatments fail to eliminate HBV genomic reservoirs, which persist as cccDNA. 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.