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Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes
Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 years of TDF tre...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914950/ https://www.ncbi.nlm.nih.gov/pubmed/33562603 http://dx.doi.org/10.3390/ijms22041606 |
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author | Lee, Ah Ram Cho, Ju-Yeon Kim, Jong Chul Dezhbord, Mehrangiz Choo, Soo Yeun Ahn, Chang Hyun Kim, Na Yeon Shin, Jae Jin Park, Soree Park, Eun-Sook Won, Juhee Kim, Dong-Sik Lee, Jeong-Hoon Kim, Kyun-Hwan |
author_facet | Lee, Ah Ram Cho, Ju-Yeon Kim, Jong Chul Dezhbord, Mehrangiz Choo, Soo Yeun Ahn, Chang Hyun Kim, Na Yeon Shin, Jae Jin Park, Soree Park, Eun-Sook Won, Juhee Kim, Dong-Sik Lee, Jeong-Hoon Kim, Kyun-Hwan |
author_sort | Lee, Ah Ram |
collection | PubMed |
description | Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 years of TDF treatment. Clonal analysis of hepatitis B virus (HBV) isolated from sequential sera of this patient identified the seven previously reported TDF-resistant mutations (CYELMVI). Interestingly, a threonine to alanine mutation at the 301 amino acid position of the reverse-transcriptase (RT) domain, (rtT301A), was commonly accompanied with CYELMVI at a high rate (72.7%). Since the rtT301A mutation has not been reported yet, we investigated the role of this naturally occurring mutation on the viral replication and susceptibility to tenofovir in various liver cells (hepatoma cells as well as primary human hepatocytes). A cell-based phenotypic assay revealed that the rtT301A mutation dramatically impaired the replication ability with meaningful reduction in sensitivity to tenofovir in hepatoma cell lines. However, attenuated viral replication by the rtT301A mutation was significantly restored in primary human hepatocytes (PHHs). Our findings suggest that the replication capability and drug sensitivity of HBV is different between hepatoma cell lines and PHHs. Therefore, our study emphasizes that validation studies should be performed not only in the liver cancer cell lines but also in the PHHs to understand the exact viral fitness under antiviral pressure in patients. |
format | Online Article Text |
id | pubmed-7914950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79149502021-03-01 Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes Lee, Ah Ram Cho, Ju-Yeon Kim, Jong Chul Dezhbord, Mehrangiz Choo, Soo Yeun Ahn, Chang Hyun Kim, Na Yeon Shin, Jae Jin Park, Soree Park, Eun-Sook Won, Juhee Kim, Dong-Sik Lee, Jeong-Hoon Kim, Kyun-Hwan Int J Mol Sci Article Tenofovir disoproxil fumarate (TDF) has been regarded as the most potent drug for treating patients with chronic hepatitis B (CHB). However recently, viral mutations associated with tenofovir have been reported. Here, we found a CHB patient with suboptimal response after more than 4 years of TDF treatment. Clonal analysis of hepatitis B virus (HBV) isolated from sequential sera of this patient identified the seven previously reported TDF-resistant mutations (CYELMVI). Interestingly, a threonine to alanine mutation at the 301 amino acid position of the reverse-transcriptase (RT) domain, (rtT301A), was commonly accompanied with CYELMVI at a high rate (72.7%). Since the rtT301A mutation has not been reported yet, we investigated the role of this naturally occurring mutation on the viral replication and susceptibility to tenofovir in various liver cells (hepatoma cells as well as primary human hepatocytes). A cell-based phenotypic assay revealed that the rtT301A mutation dramatically impaired the replication ability with meaningful reduction in sensitivity to tenofovir in hepatoma cell lines. However, attenuated viral replication by the rtT301A mutation was significantly restored in primary human hepatocytes (PHHs). Our findings suggest that the replication capability and drug sensitivity of HBV is different between hepatoma cell lines and PHHs. Therefore, our study emphasizes that validation studies should be performed not only in the liver cancer cell lines but also in the PHHs to understand the exact viral fitness under antiviral pressure in patients. MDPI 2021-02-05 /pmc/articles/PMC7914950/ /pubmed/33562603 http://dx.doi.org/10.3390/ijms22041606 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Ah Ram Cho, Ju-Yeon Kim, Jong Chul Dezhbord, Mehrangiz Choo, Soo Yeun Ahn, Chang Hyun Kim, Na Yeon Shin, Jae Jin Park, Soree Park, Eun-Sook Won, Juhee Kim, Dong-Sik Lee, Jeong-Hoon Kim, Kyun-Hwan Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes |
title | Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes |
title_full | Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes |
title_fullStr | Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes |
title_full_unstemmed | Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes |
title_short | Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes |
title_sort | distinctive hbv replication capacity and susceptibility to tenofovir induced by a polymerase point mutation in hepatoma cell lines and primary human hepatocytes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914950/ https://www.ncbi.nlm.nih.gov/pubmed/33562603 http://dx.doi.org/10.3390/ijms22041606 |
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