Hepatitis B virus covalently closed circular DNA homeostasis is independent of the lymphotoxin pathway during chronic HBV infection.
Current treatment options for patients with chronic hepatitis B virus (HBV) infection are not curative as they are not effective in eliminating covalently closed circular DNA (cccDNA). cccDNA is a stable template for HBV transcription in the nucleus of hepatocytes and is thought to be one of the main factors responsible for HBV persistence. Recently, activation of the lymphotoxin beta receptor (LTβR) has been shown to trigger degradation of cccDNA through induction of cytidine deaminases of the APOBEC3 family in HBV cell culture model systems. To assess the presence and relevance of such mechanisms in the liver of chronically HBV-infected patients, we compared intrahepatic cccDNA levels with the expression levels of lymphotoxins and some of their target genes (eg APOBEC deaminases) in liver biopsy tissue. Our results confirm elevated gene expression levels of components of the lymphotoxin pathway including lymphotoxin alpha (LTα), lymphotoxin beta (LTβ), APOBEC3B (A3B) and APOBEC3G (A3G) in the chronically HBV-infected liver compared to uninfected liver. Furthermore, expression levels of the genes of the APOBEC deaminase family were correlated with those of LTα and LTβ gene expression, consistent with lymphotoxin-mediated upregulation of APOBEC gene expression. However, intrahepatic cccDNA and HBV replication levels were not correlated with LTα, LTβ and APOBEC gene expression. In conclusion, these results suggest that although the lymphotoxin pathway is activated in the chronically HBV-infected liver, it has no major impact on HBV cccDNA metabolism in chronic HBV infection.
Department of Biomedicine, University Hospital (USB), University of Basel, Basel, Switzerland.
M-A
MA
Meier
Department of Biomedicine, University Hospital (USB), University of Basel, Basel, Switzerland.
A
A
Suslov
Department of Biomedicine, University Hospital (USB), University of Basel, Basel, Switzerland.
S
S
Ketterer
Department of Biomedicine, University Hospital (USB), University of Basel, Basel, Switzerland.|Division of Gastroenterology and Hepatology, University Hospital (USB), University of Basel, Basel, Switzerland.
M H
MH
Heim
Department of Biomedicine, University Hospital (USB), University of Basel, Basel, Switzerland.
S F
0000-0002-4444-977X
SF
Wieland
D003564:Cytidine Deaminase / Q000378:metabolism; D004270:DNA, Circular / Q000032:analysis*; D020869:Gene Expression Profiling; D006515:Hepatitis B virus / Q000254:growth & development* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000473:pathology* / Q000821:virology*; D006706:Homeostasis; D006801:Humans; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000378:metabolism*
D004270:DNA, Circular; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D003564:Cytidine Deaminase
APOBEC3; cccDNA degradation; hepatitis B virus; human liver biopsy; lymphotoxin