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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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