Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment
Tanner Grudda, … , Ashwin Balagopal, Chloe L. Thio
Tanner Grudda, … , Ashwin Balagopal, Chloe L. Thio
Published July 7, 2022
Citation Information: J Clin Invest. 2022;132(18):e161818. https://doi.org/10.1172/JCI161818.
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Research Article Infectious disease Virology

Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment

Abstract

The focus of hepatitis B functional cure, defined as sustained loss of hepatitis B virus (HBV) 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 droplet digital PCR 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 analog (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 3 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.

Authors

Tanner Grudda, Hyon S. Hwang, Maraake Taddese, Jeffrey Quinn, Mark S. Sulkowski, Richard K. Sterling, Ashwin Balagopal, Chloe L. Thio

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Figure 4

HBsAg decline during NUC treatment and iDNA-derived transcription.

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HBsAg decline during NUC treatment and iDNA-derived transcription. Box-a...
Box-and-whisker plots represent the summarized serum HBsAg levels at the time of each biopsy for people who achieved a >0.5 log10 IU/mL decline (left panel, n = 4) and those who had ≤0.5 log10 IU/mL (right panel, n = 12). The absolute HBsAg levels are shown on the leftward y axis and are visualized as the salmon-colored box-and-whiskers plots. The central horizontal line for each box-and-whisker denotes the median HBsAg amounts, while the box demarcates the interquartile range of the data. The whiskers extend to encompass ± 1.5 × IQR of the data. Data points (open purple circles) corresponding to the contemporaneous liver measurements of the iDNA transcriptional index (iDNA TI) from the same people are overlaid and quantified by the rightward y axis (n = 32). A horizontal cutoff (purple line) indicates a sample for which the majority of HBV transcripts derive from iDNA since an iDNA TI > 2 indicates that more transcripts derive from iDNA than from cccDNA. Bx1, biopsy 1; Bx2, biopsy 2.