{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:47:00Z","timestamp":1760233620402,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22041606","type":"journal-article","created":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T08:33:48Z","timestamp":1612514028000},"page":"1606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Distinctive HBV Replication Capacity and Susceptibility to Tenofovir Induced by a Polymerase Point Mutation in Hepatoma Cell Lines and Primary Human Hepatocytes"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6075-3352","authenticated-orcid":false,"given":"Ah Ram","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Yeon","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, College of Medicine, Chosun University, Gwangju 61452, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Chul","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-2084","authenticated-orcid":false,"given":"Mehrangiz","family":"Dezhbord","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soo Yeun","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang Hyun","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na Yeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Jin","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0500-2227","authenticated-orcid":false,"given":"Soree","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun-Sook","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Konkuk University, Seoul 05029, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juhee","family":"Won","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0608-1580","authenticated-orcid":false,"given":"Dong-Sik","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of HBP Surgery and Liver Transplantation, College of Medicine, Korea University, Seoul 02841, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0315-2080","authenticated-orcid":false,"given":"Jeong-Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Liver Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-072X","authenticated-orcid":false,"given":"Kyun-Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1016\/S0140-6736(14)60220-8","article-title":"Hepatitis B virus 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