Abstract
Previous studies identified APOBEC deaminases as enzymes targeting hepatitis B virus (HBV) DNA in the nucleus thus affecting its persistence. Interferon (IFN)-α treated chimpanzees and hepatitis C patients showed elevated APOBEC expression. We thus hypothesized that the responses to IFN-α treatment of chronic hepatitis B (CHB) patients is influenced by IFN-induced base excision repair (BER). CHB-treatment naïve patients, patients treated with PEGylated IFN-α, and patients with sequential treatment of Entecavior and PEGylated IFN-α were recruited. Blood and liver biopsy samples were collected before treatment and at treatment endpoint. BER genes were assessed by quantitative RT-PCR. BER gene expression levels and IFN treatment responses were correlated in patient liver biopsies. APOBEC3A, -B, -C, -D/E, and-G mRNA levels were up-regulated in IFN-treated patients. APOBEC3A expression was significantly higher in IFN-responders than in non-responders. BER genes NEIL3 was down-regulated in IFN-treated patients. APOBEC3 and BER gene expression at treatment endpoints partially correlated with the corresponding absolute DNA level or degree of HBsAg and HBV DNA decline. Our study suggests that the expression of APOBEC3A positively correlates with IFN-treatment responses in CHB patients, while NEIL3 shows negative correlation. These genes may involve to IFN mediated viral suppression and serve as biomarkers for CHB disease management.
Highlights
IFN-α induced APOBEC3A deaminates the nuclear hepatitis B virus (HBV) DNA minus strand, resulting uracil-containing DNA that recognized, cleaved and degraded by cellular base excision repair (BER) enzymes
We report that in particular the expression levels of DNA-editing enzymes APOBEC3A, and BER gene NEIL3 correlate with response to IFN treatment in chronic hepatitis B (CHB) patients
We found that APOBEC3A, -B,C,DE, and -G mRNA expression were significantly induced in livers of patients treated with IFN-α compared to treatment-naïve patients or OSST patients[1] before IFN-α treatment (Fig. 1B), while APOBEC3F and APOBEC3H were only up-regulated in three patients (Fig. 1C)
Summary
IFN-α induced APOBEC3A deaminates the nuclear HBV DNA minus strand, resulting uracil-containing DNA that recognized, cleaved and degraded by cellular BER enzymes. APOBEC3A was found to be up-regulated in IFN-α treated chimpanzee and chronic hepatitis C patient livers[10], the expression profiles of APOBEC3 family members as well as BER genes and their correlation with IFN-α treatment response in patients with CHB has not been addressed. We report that in particular the expression levels of DNA-editing enzymes APOBEC3A, and BER gene NEIL3 correlate with response to IFN treatment in CHB patients. These genes indicate the molecular pathways involved in HBV cure but may serve as biomarkers for CHB disease management
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