Failure of current
therapies to cure
chronic hepatitis B has led to renewed interest in
therapies that stimulate the host immune system. APOBEC3 (A3) family
enzymes have been shown to induce mutations in hepatitis B virus (HBV) covalently closed
circular DNA (cccDNA) leading to inhibition of HBV transcription and replication.
Pattern recognition receptor (PRR) agonists have been reported to suppress HBV, but it is unclear whether these agonists induce A3 gene expression in hepatocytes. We, therefore, evaluated whether PRR signaling activates the expression of A3 genes and other innate immunity genes and restricts HBV
infection. HepG2-sodium
taurocholate cotransporting
polypeptide (NTCP) cells were infected with HBV and treated with various PRR agonists. The level of HBV
infection was subsequently assessed by measurement of HBV
biomarkers, including HBV
DNA, cccDNA, HBs, and HBe
antigens in infected hepatocytes. Among all tested PRR
ligands, only
Poly(I:C)-HMW/LyoVec and
Poly(I:C)-HMW significantly inhibited
hepatitis B surface antigen (
HBsAg),
hepatitis B e antigen (
HBeAg), HBV
DNA, and cccDNA, whereas R848 and
lipopolysaccharide (LPS) only showed significant inhibition on
HBsAg and
HBeAg, but not virus DNA. CpG and Pam3CSK4, on the other hand, had no significant inhibitory effect on any of the HBV
infection parameters. Moreover,
Poly(I:C)-HMW/LyoVec and
Poly(I:C)-HMW were the only
ligands that significantly increased
IL-8 secretion. Interestingly, HBV
infection reduced
IL-8 secretion induced by
Poly(I:C)-HMW and to a lesser extent
Poly(I:C)-HMW/LyoVec.
Poly(I:C)-HMW/LyoVec had a significant effect on increasing the expression level of A3F, A3G, A3H, TLR3, RIG-1, and MDA5 genes. Our data suggest that PRR agonists may control HBV
infection through different mechanisms. The RIG-1 and MDA5 agonist,
Poly(I:C)-HMW/LyoVec, seems to downregulate HBV
infection through induction of A3 genes.