Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment
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 D...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI161818 |
| _version_ | 1797634580477378560 |
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| author | Tanner Grudda Hyon S. Hwang Maraake Taddese Jeffrey Quinn Mark S. Sulkowski Richard K. Sterling Ashwin Balagopal Chloe L. Thio |
| author_facet | Tanner Grudda Hyon S. Hwang Maraake Taddese Jeffrey Quinn Mark S. Sulkowski Richard K. Sterling Ashwin Balagopal Chloe L. Thio |
| author_sort | Tanner Grudda |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:37Z |
| format | Article |
| id | doaj.art-4ae31255e99b4eb3a92cbb60ecbdf52f |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:37Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-4ae31255e99b4eb3a92cbb60ecbdf52f2023-11-07T16:19:20ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-09-0113218Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatmentTanner GruddaHyon S. HwangMaraake TaddeseJeffrey QuinnMark S. SulkowskiRichard K. SterlingAshwin BalagopalChloe L. ThioThe 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.https://doi.org/10.1172/JCI161818Infectious diseaseVirology |
| spellingShingle | Tanner Grudda Hyon S. Hwang Maraake Taddese Jeffrey Quinn Mark S. Sulkowski Richard K. Sterling Ashwin Balagopal Chloe L. Thio Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment The Journal of Clinical Investigation Infectious disease Virology |
| title | Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment |
| title_full | Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment |
| title_fullStr | Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment |
| title_full_unstemmed | Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment |
| title_short | Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment |
| title_sort | integrated hepatitis b virus dna maintains surface antigen production during antiviral treatment |
| topic | Infectious disease Virology |
| url | https://doi.org/10.1172/JCI161818 |
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