Mechanisms of Lymphotoxin-beta Receptor Agonization induced upregulation of the anti-HBV host restriction factor APOBEC3B

Chronic infection with hepatitis B virus (HBV) remains a serious health problem, although a protective vaccination is available. Over 250 million people are infected worldwide, and HBV is responsible for more than 800.000 deaths per year, mostly results of liver cirrhosis and hepatocellular carcinoma.

In the clinic, chronic hepatitis B (CBH) can be treated with nucleotide or nucleoside analogues, which efficiently suppress HBV replication; however, upon withdrawal of the drug, the infection relapses, as the genome of the virus, the covalently closed circular DNA (cccDNA) is not removed from the nucleus of the hepatocyte. It had been shown, that treatment with PEG-IFNα can lead to eradication of the cccDNA, however, this is dose-dependent. The dose if interferon needed to achieve the degradation of the virus is so high, that severe side effects occur often.

In 2014, we published an article shedding light on a possible new approach to fight HBV infection. We observed, that stimulation of cells in vitro with BS1, an antibody that agonizes the lymphotoxin beta receptor (LTβR) on the surface of HBV infected hepatocytes, leads to the degradation of cccDNA and suppression of the infection, directly linked to the upregulation of APOBEC3B, a cytidine deaminase.

We analysed mechanisms of the upregulation of APOBEC3B, which will be important to know, if treatment with LTβR agonists of CBH patients in the future is considered. We found, that APOBEC3B upregulation after LTβR agonization is dependent on classical and alternative NFκB signalling, via IKKβ and via NIK, respectively. We further found that miRNA-138 – 5 p is a post-transcriptional repressor of APOBEC3B, which is negatively regulated by LTβR agonization. Finally, we investigated the effects of oxygen levels on APOBEC3B expression, and described a HIF1α-dependant negative effect of low oxygen levels on APOBEC3B expression, both in CBH patients, as well as in in vitro studies.