Hbv Integration can Sustain Intrahepatic Hdv Activity and can Modulate Hbv Pathogenetic Potential
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Authors
D'Anna S.
Piermatteo L.
Di Lorenzo A.
Carioti L.
Brancaccio G.
Teti E.
Grossi I.
Castelli C.
Magnapera A.
Malagnino V.
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Issue Date
2025
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Conference Proceedings
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Background HDV depends on HBsAg for its infectivity. HBsAg can derive from cccDNA and also from the integration of the so-called linear HBV-DNA in the genome of infected hepatocytes. Here, we elucidate the contribution of HBsAg production from linear HBV-DNA integration in sustaining HDV activity and its pathogenetic potential. Material and Methods 70 liver biopsies from eAg-negative individuals (74% NUC-treated) were included: 35 with CHB and 35 with CHD. Droplet-digital PCR was used to quantify intrahepatic levels of cccDNA, pgRNA, HDV-RNA and HBs transcripts from cccDNA and from integrated HBV-DNA (Grudda, 2022). Next-generation sequencing by Illumina was applied to assess the integration of linear HBV-DNA in hepatocytes' genome (in 22 CHB and 32 CHD). Results Individuals with CHD and CHB had comparable age and NUC-treatment duration. CHD was characterized by lower cccDNA and pgRNA than CHB (median [IQR]: 1 [0.02-12] vs 24 [8-93] copies (cps)/1000 cells and 8 [1-147] vs 518 [57-3,894] cps/1000cells, P99% of them from integrated HBV-DNA (median [IQR] cps/1000cells: 12,776 [4,570-55,977] in CHB and 6,041 [323-29,446] in CHD). Among the 427 HBV-integration events observed in CHD, 180 involved coding regions of the hepatocytes' genome, corresponding to a median (IQR) number of 5 (2-10) unique events per patient. Notably, the number of HBV-integration events in coding regions showed a positive correlation with the amount of integration-derived HBsAg transcripts and with serum HBsAg (Rho=0.54 and 0.64, P4 logIU/ml; P=0.01). In 19/25 individuals with CHD characterized by >1 HBVintegration event, HBV-DNA integrants localised in human genes regulating cell proliferation. Among the 60 genes identified, 40 genes are already known to be specifically involved in hepatocarcinogenesis. Conclusions HDV persistence is independent from the intrahepatic HBV reservoir and is sustained by HBsAg production from integrated HBV-DNA. Higher HBsAg levels (>4logIU/ml) can reflect an enrichment of HBV-DNA integration events in coding regions of hepatocytes' genome. Localization of HBV integrants suggests that these events may potentially induce hepatocytes proliferation, paving the way for carcinogenesis.
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Sexually Transmitted Infections