Enrichment Reveals Extensive Integration of Hepatitis B Virus DNA in Hepatitis Delta Virus-Infected Patients

• Published in: The Journal of infectious diseases Vol. 230; no. 3; pp. e684 - e693
• Main Authors: Ringlander, Johan, Strömberg, Lucia Gonzales, Stenbäck, Joakim B, Andersson, Maria E, Abrahamsson, Sanna, Skoglund, Catarina, Castedal, Maria, Larsson, Simon B, Rydell, Gustaf E, Lindh, Magnus
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 23.09.2024
• Subjects: Cirrhosis; deep sequencing; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA viruses; HBsAg; HBV integrations; HBV RNA enrichment; Hepatitis B; Hepatitis B surface antigen; hepatitis B virus; Hepatitis delta virus; Hepatocytes; Immunologi inom det medicinska området; Immunology in the Medical Area; Liver; Liver cirrhosis; Major; Serum levels; HBV RNA enrichment; HBsAg; deep sequencing; hepatitis B virus; hepatitis delta virus; HBV integrations
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiae045

Abstract Background Hepatitis B virus (HBV) DNA may become integrated into the human genome of infected human hepatocytes. Expression of integrations can produce the surface antigen (HBsAg) that is required for synthesis of hepatitis D virus (HDV) particles and the abundant subviral particles in the blood of HBV- and HDV-infected subjects. Knowledge about the extent and variation of HBV integrations and impact on chronic HDV is still limited. Methods We investigated 50 pieces of liver explant tissue from 5 patients with hepatitis D-induced cirrhosis, using a deep-sequencing strategy targeting HBV RNA. Results We found that integrations were abundant and highly expressed, with large variation in the number of integration-derived (HBV/human chimeric) reads, both between and within patients. The median number of unique integrations for each patient correlated with serum levels of HBsAg. However, most of the HBV reads represented a few predominant integrations. Conclusions The results suggest that HBV DNA integrates in a large proportion of hepatocytes, and that the HBsAg output from these integrations vary >100-fold depending on clone size and expression rate. A small proportion of the integrations seems to determine the serum levels of HBsAg and HDV RNA in HBV/HDV coinfected patients with liver cirrhosis. Explant tissue deep RNA sequencing showed that HBV DNA integrates extensively, but great variation in S-RNA levels suggests that a small part of the integrations determines serum levels of HBsAg and HDV RNA in HBV/HDV coinfected patients with liver cirrhosis.