Integrated hepatitis B virus DNA maintains surface antigen production during antivirals
Tanner Grudda 1 , Hyon S Hwang 2 , Maraake Taddese 2 , Jeffrey Quinn 2 , Mark S Sulkowski 2 , Richard K Sterling 3 , Ashwin Balagopal 2 , Chloe L Thio 1
Affiliations
Affiliations
1
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America.
2
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America.
3
Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University, Richmond, United States of America.
PMID: 35797115 DOI: 10.1172/JCI161818
Free article
Abstract
The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B surface antigen (HBsAg) and HBV DNA from blood, is on eliminating or silencing the intranuclear template for HBV replication, covalently closed circular DNA (cccDNA). However, HBsAg also derives from HBV DNA integrated into the host genome (iDNA). Little is known about the contribution of iDNA to circulating HBsAg with current therapeutics. We applied a multiplex ddPCR assay to demonstrate that iDNA is responsible for maintaining HBsAg quantities in some individuals. Using paired bulk liver tissue from 16 HIV/HBV coinfected persons on nucleos(t)ide analogue (NUC) therapy, we demonstrate that people with larger HBsAg declines between biopsies derive HBsAg from cccDNA whereas people with stable HBsAg levels derive predominantly from iDNA. We applied our assay to individual hepatocytes in paired tissues from three people and demonstrated that the individual with significant HBsAg decline had a commensurate loss of infected cells with transcriptionally active cccDNA, while individuals without HBsAg decline had stable or increasing numbers of cells producing HBsAg from iDNA. We demonstrate that while NUC therapy may be effective at controlling cccDNA replication and transcription, innovative treatments are required to address iDNA transcription that sustains HBsAg production.