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Detection of Low Copy Number Integrated Viral DNA Formed by In Vitro Hepatitis B Infection
Published on: November 7, 2018
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Complex genetic encoding of the hepatitis B virus on-drug persistence
Hong Thai1, James Lara2, Xiaojun Xu2,3
1Division of Viral Hepatitis, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA, 30329, USA. guy8@cdc.gov.
Scientific Reports
|September 24, 2020
Summary
Hepatitis B virus (HBV) persistence during tenofovir disoproxil fumarate (TDF) therapy is linked to widespread genetic variations across the entire HBV genome, not just specific mutations. These variations impact TDF efficacy without causing true resistance.
Area of Science:
- Virology
- Molecular Biology
- Pharmacogenomics
Background:
- Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used to treat HIV and Hepatitis B virus (HBV) infections.
- While no true resistance to TDF in HBV is known, variable viral persistence suggests underlying genetic factors influencing drug efficacy.
- Understanding these factors is crucial for optimizing HBV treatment strategies.
Purpose of the Study:
- To investigate the genetic mechanisms behind HBV on-drug persistence during TDF therapy.
- To differentiate genetic factors contributing to rapid versus slow viral response to TDF.
- To explore the role of intra-host HBV genetic variation in TDF efficacy.
Main Methods:
- Whole-genome sequencing of 1,288 intra-host HBV variants from patients with rapid and slow responses to TDF.
- Phylogenetic analysis to assess the association of genomic and protein polymorphic sites with TDF response.
- Bayesian network methods to model genetic associations.
- 3D-structure analysis of reverse transcriptase (RT) binding affinity.
Main Results:
- HBV on-TDF persistence is associated with genetic variations across the entire HBV genome, unlike typical drug resistance mutations in RT.
- No significant difference in TDF binding affinity to RT was observed between rapidly declining and persistent HBV variants.
- Genetic associations with TDF response varied between HBV genotypes B and C, indicating complex genetic control.
- No single mutation pattern defined TDF-sensitive intra-host variants.
Conclusions:
- HBV on-drug persistence during TDF therapy is driven by complex, genome-wide genetic mechanisms rather than specific RT mutations.
- TDF binding affinity to RT does not appear to be the primary determinant of on-drug persistence.
- These findings suggest that multiple, differentially available genetic mechanisms contribute to HBV's robustness against TDF, potentially impacting overall treatment effectiveness.
- Further research into these mechanisms is needed for developing more potent anti-HBV drugs.
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