Soree Park1, Eun-Sook Park1, Ja Eun Koo2, Yong Kwang Park1, Ah Ram Lee1, Mehrangiz Dezhbord1, Eun Sook Cho1, Sung Hyun Ahn1, Doo Hyun Kim1, Jeong-Hoon Lee3, Han Chu Lee2, Kyun-Hwan Kim1,4. 1. Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea. 2. Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. 3. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea. 4. Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, Korea.
Abstract
BACKGROUND AND AIM: Since polymerase and surface genes overlap in hepatitis B virus (HBV), an antiviral-induced mutation in the polymerase gene may alter the surface antigenicity in patients with chronic hepatitis B (CHB), but this possibility has not been clearly confirmed. This study aimed to determine the drug susceptibility and surface antigenicity of the patient-derived mutants. PATIENTS AND METHODS: Full-length HBV genomes isolated from four entecavir-resistant CHB patients were cloned and sequenced. Around 10 clones of full-length HBV obtained from each patient were analysed and registered in the NCBI GenBank. Representative clones were further characterized by in vitro drug susceptibility and surface antigenicity assays. RESULTS: The rtL180M + rtM204V mutations were common among all the clones analysed. Additionally, the ETV resistance mutations rtT184A/L, rtS202G and rtM250V were found among three patients. Most of the ETV-resistant mutants had amino acid alterations within the known epitopes recognized by T- and B-cells in the HBV surface and core antigens. The in vitro drug susceptibility assay showed that all tested clones were resistant to ETV treatment. However, they were all susceptible to ADV and TDF. More importantly, the rtI169T mutation in the RT domain, led to the sF161L mutation in the overlapping S gene, which decreased in surface antigenicity. CONCLUSIONS: The ETV resistance mutations can affect the antigenicity of the HBsAg proteins due to changes in the overlapping sequence of this surface antigen. Thus, the apparent decline or disappearance of HBsAg needs to be interpreted cautiously in patients with previous or current antiviral resistance mutations.
BACKGROUND AND AIM: Since polymerase and surface genes overlap in hepatitis B virus (HBV), an antiviral-induced mutation in the polymerase gene may alter the surface antigenicity in patients with chronic hepatitis B (CHB), but this possibility has not been clearly confirmed. This study aimed to determine the drug susceptibility and surface antigenicity of the patient-derived mutants. PATIENTS AND METHODS: Full-length HBV genomes isolated from four entecavir-resistant CHBpatients were cloned and sequenced. Around 10 clones of full-length HBV obtained from each patient were analysed and registered in the NCBI GenBank. Representative clones were further characterized by in vitro drug susceptibility and surface antigenicity assays. RESULTS: The rtL180M + rtM204V mutations were common among all the clones analysed. Additionally, the ETV resistance mutations rtT184A/L, rtS202G and rtM250V were found among three patients. Most of the ETV-resistant mutants had amino acid alterations within the known epitopes recognized by T- and B-cells in the HBV surface and core antigens. The in vitro drug susceptibility assay showed that all tested clones were resistant to ETV treatment. However, they were all susceptible to ADV and TDF. More importantly, the rtI169T mutation in the RT domain, led to the sF161L mutation in the overlapping S gene, which decreased in surface antigenicity. CONCLUSIONS: The ETV resistance mutations can affect the antigenicity of the HBsAg proteins due to changes in the overlapping sequence of this surface antigen. Thus, the apparent decline or disappearance of HBsAg needs to be interpreted cautiously in patients with previous or current antiviral resistance mutations.
Authors: Jong Chul Kim; Hye Young Lee; Ah Ram Lee; Mehrangiz Dezhbord; Da Rae Lee; Seong Ho Kim; Juhee Won; Soree Park; Na Yeon Kim; Jae Jin Shin; Sang Gyune Kim; Young Seok Kim; Jeong-Ju Yoo; Kyun-Hwan Kim Journal: Biomedicines Date: 2022-01-26
Authors: Timothy S Buhlig; Anastasia F Bowersox; Daniel L Braun; Desiree N Owsley; Kortney D James; Alfredo J Aranda; Connor D Kendrick; Nicole A Skalka; Daniel N Clark Journal: Viruses Date: 2020-05-22 Impact factor: 5.048