Journal article
Estimation of hepatitis B virus cccDNA persistence in chronic infection using within-host evolutionary rates
- Abstract:
- Hepatitis B virus (HBV) infection is a major global health problem with over 240 million infected individuals at risk of developing progressive liver disease and hepatocellular carcinoma. HBV is an enveloped DNA virus that establishes its genome as an episomal, covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Currently available standard-of-care treatments for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NA) that suppress HBV replication but do not target the cccDNA and hence rarely cure infection. There is considerable interest in determining the lifespan of cccDNA molecules to design and evaluate new curative treatments. We took a novel approach to this problem by developing a new mathematical framework to model changes in evolutionary rates during infection which, combined with previously determined within-host evolutionary rates of HBV, we used to determine the lifespan of cccDNA. We estimate that during HBe-antigen positive (HBeAgPOS) infection the cccDNA lifespan is 61 (36-236) days, whereas during the HBeAgNEG phase of infection it is only 26 (16-81) days. We found that cccDNA replicative capacity declined by an order of magnitude between HBeAgPOS and HBeAgNEG phases of infection. Our estimated lifespan of cccDNA is too short to explain the long durations of chronic infection observed in patients on NA treatment, suggesting that either a sub-population of long-lived hepatocytes harbouring cccDNA molecules persists during therapy, or that NA therapy does not suppress all viral replication. These results provide a greater understanding of the biology of the cccDNA reservoir and can aid the development of new curative therapeutic strategies for treating CHB.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Supplementary materials, 152.8KB, Terms of use)
-
(Preview, Version of record, 834.5KB, Terms of use)
-
- Publisher copy:
- 10.1093/ve/veaa063
Authors
- Publisher:
- Oxford University Press
- Journal:
- Virus Evolution More from this journal
- Volume:
- 7
- Issue:
- 1
- Article number:
- veaa063
- Publication date:
- 2020-08-25
- Acceptance date:
- 2020-07-10
- DOI:
- EISSN:
-
2057-1577
- Language:
-
English
- Keywords:
- Pubs id:
-
1087324
- Local pid:
-
pubs:1087324
- Deposit date:
-
2020-06-22
Terms of use
- Copyright holder:
- Lythgoe et al.
- Copyright date:
- 2020
- Rights statement:
- © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record