Proceedings of the National Academy of Sciences of the United States of America
| العنوان: | Proceedings of the National Academy of Sciences of the United States of America |
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| المؤلفون: | Bo Wang, Debin Tian, Harini Sooryanarain, Hassan M. Mahsoub, C. Lynn Heffron, Anna M. Hassebroek, Xiang-Jin Meng |
| المصدر: | Proceedings of the National Academy of Sciences. 119 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | genotype 3 HEV (HEV-3), Multidisciplinary, Genotype, fulminant hepatic failure (FHF), hepatitis E Virus (HEV), Liver Failure, Acute, Virus Replication, Hepatitis E, Pregnancy, Mutation, Ribavirin, Hepatitis E virus, Humans, Female, genotype 1 HEV (HEV-1), FHF-associated HEV-1 mutations |
| الوصف: | Hepatitis E virus (HEV) infection in pregnant women has a high incidence of developing fulminant hepatic failure (FHF) with significant mortality. Multiple amino acid changes in genotype 1 HEV (HEV-1) are reportedly linked to FHF clinical cases, but experimental confirmation of the roles of these changes in FHF is lacking. By utilizing the HEV-1 indicator replicon and infectious clone, we generated 11 HEV-1 single mutants, each with an individual mutation, and investigated the effect of these mutations on HEV replication and infection in human liver cells. We demonstrated that most of the mutations actually impaired HEV-1 replication efficiency compared with the wild type (WT), likely due to altered physicochemical properties and structural conformations. However, two mutations, A317T and V1120I, significantly increased HEV-1 replication. Notably, these two mutations simultaneously occurred in 100% of 21 HEV-1 variants from patients with FHF in Bangladesh. We further created an HEV-1 A317T/V1120I double mutant and found that it greatly enhanced HEV replication, which may explain the rapid viral replication and severe disease. Furthermore, we tested the effect of these FHF-associated mutations on genotype 3 HEV (HEV-3) replication and found that all the mutants had a reduced level of replication ability and infectivity, which is not unexpected due to distinct infection patterns between HEV-1 and HEV-3. Additionally, we demonstrated that these FHF-associated mutations do not appear to alter their sensitivity to ribavirin (RBV), suggesting that ribavirin remains a viable option for antiviral therapy for patients with FHF. The results have important implications for understanding the mechanism of HEV-1-associated FHF. NIH [R01 AI050611] Published version We thank Dr. Sue Emerson (NIAID, NIH) for kindly providing the HEV-1 Sar55 and HEV-3 p6 infectious clones, HEV-3 p6 Gaussia luciferase indicator replicon, and Huh7-S10-3 cells. We also thank Dr. Alexander Ploss (Princeton University) for kindly providing the HEV-1 Sarr55 Gaussia luciferase indicator replicon. The authors' research on HEV is funded by a grant from the NIH (R01 AI050611). |
| وصف الملف: | application/pdf |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::90fb04cf1cf71b30b09020571c08cf12 https://doi.org/10.1073/pnas.2207503119 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....90fb04cf1cf71b30b09020571c08cf12 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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