RNA interference-mediated control of hepatitis B virus and emergence of resistant mutant
Autor: | Ding-Shinn Chen, Hsiao-Lei Lai, Li-Rung Huang, Chuan-Chuan Huang, Yu-Tzu Huang, Chun-Jen Liu, Cheng-Yi Lu, Yun-Wei Hsu, Hui-Lin Wu, Pei-Jer Chen |
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Rok vydání: | 2005 |
Předmět: |
Small interfering RNA
Hepatitis B virus Genotype Gene Expression Viral quasispecies Biology medicine.disease_cause Transfection Virus Replication Article Hepatitis B virus PRE beta Cell Line Small hairpin RNA Mice Plasmid RNA interference Drug Resistance Viral medicine Animals Humans RNA Small Interfering Hepatology Base Sequence Gastroenterology virus diseases RNA Virology Molecular biology digestive system diseases Mice Inbred C57BL RNAi RNA interference siRNA small interfering RNA Mutation shRNA short hairpin RNA RNA Interference |
Zdroj: | Gastroenterology |
ISSN: | 0016-5085 |
Popis: | Background & Aims Present therapy for chronic hepatitis B attains control only in limited proportions. Small interfering RNA (siRNA) offers a new tool with potential therapeutic applications for hepatitis B virus (HBV). Given the importance of sequence identity in the effectiveness of siRNA and the heterogeneity of HBV sequences among different isolates, a short hairpin RNA (shRNA)-expressing plasmid, pSuper/HBVS1, was developed to target a region conserved among major HBV genotypes and assess its effectiveness control of HBV. Methods HBV replication-competent plasmid was cotransfected with pSuper/HBVS1 to HuH-7 cells or to mice. The levels of viral proteins, RNA, and DNA were examined in transfected cells and animals. The effects of pSuper/HBVS1 on clinical isolates with genotypes B and C were also determined. Results pSuper/HBVS1 significantly decreased levels of viral proteins, RNA, and DNA for HBV genotype A in cell culture and in mice. Comparable suppressive effects were observed on clinical isolates of genotypes B and C. A clone with a silent mutation in the target region was identified from a patient with genotype C. This mutant revealed diminished sensitivity to pSuper/HBVS1 and could be selected out in the presence of pSuper/HBVS1 in cell culture. Conclusions These findings indicated that shRNA could suppress HBV expression and replication for genotypes A, B, and C, promising an advance in treatment of HBV. However, the emergence of resistant mutants in HBV quasispecies should be considered. |
Databáze: | OpenAIRE |
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