Difluoromethylornithine, a Decarboxylase 1 Inhibitor, Suppresses Hepatitis B Virus Replication by Reducing HBc Protein Levels.

Current treatments of hepatitis B virus (HBV) are limited to Interferon-alpha or the nucleos(t)ide analogs antiviral therapies, and it is crucial to develop and define new antiviral drugs to cure HBV. In this study, we explored the anti-HBV effect of difluoromethylornithine (DFMO), an irreversibly inhibitor of decarboxylase 1(ODC1) on HBV replication. Firstly, we found that polyamines contributed to HBV DNA replication via increasing levels of the HBV core protein (HBc) and capsids. In contrast, depletion of polyamines either by silencing the expression of ODC1 or DFMO treatment, resulted in decreasing viral DNA replication and levels of HBc protein and capsids. Furthermore, we found that DFMO decreased the stability of the HBc protein without affecting mRNA transcription and protein translation. Taken together, our findings demonstrate that DFMO inhibits HBV replication by reducing HBc stability and this may provide a new approach for HBV therapeutics.

Cyclin E2-CDK2 mediates SAMHD1 phosphorylation to abrogate its restriction of HBV replication in hepatoma cells.

SAMHD1 inhibits Hepatitis B virus (HBV) replication by reducing the intracellular dNTP levels. However, how SAMHD1 phosphorylation is regulated to abrogate its restriction of HBV replication in hepatoma cells is poorly understood. Here, we show that HBV replication and SAMHD1 phosphorylation levels are significantly reduced by knocking down cyclin-dependent kinase (CDK) 2 expression or in the presence of a CDK2 inhibitor. SAMHD1 binds to CDK2 in hepatocarcinoma cells, and this interaction does not require the HBV core protein. Furthermore, cyclin E2 participates in regulating viral replication through the CDK2/SAMHD1 phosphorylation pathway in an HBV infection system. Collectively, our results provide evidence that CDK2 has a greater role in regulating SAMHD1 phosphorylation and HBV replication than CDK1 or CDK6.