期刊
VIRUSES-BASEL
卷 14, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/v14112527
关键词
hepatitis C virus; genotype 4d; infectious culture system; direct-acting antivirals; neutralizing antibodies; human-liver chimeric mice; Huh7; 5 cells
类别
资金
- Region H Foundation
- Novo Nordisk Foundation
- Independent Research Fund Denmark (DFF), Medical Sciences
- Danish Cancer Society
- Weimann Foundation
- Lundbeck Foundation
- Danish Agency for Science and Higher Education
Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups in Europe. However, 4d infectious culture systems are not available, hindering drug studies and neutralizing antibody research relevant for HCV vaccine development. This study developed the first genotype 4d infectious culture system, enabling efficacy testing of direct-acting antivirals (DAAs) and assessment of antibody neutralization, which is critical for optimizing DAA treatments and designing vaccines to combat the HCV epidemic.
Hepatitis C virus (HCV) genotype 4 is highly prevalent in the Middle East and parts of Africa. Subtype 4d has recently spread among high-risk groups in Europe. However, 4d infectious culture systems are not available, hampering studies of drugs, as well as neutralizing antibodies relevant for HCV vaccine development. We determined the consensus 4d sequence from a chronic hepatitis C patient by next-generation sequencing, generated a full-length clone thereof (pDH13), and demonstrated that pDH13 RNA-transcripts were viable in the human-liver chimeric mouse model, but not in Huh7.5 cells. However, a JFH1-based DH13 Core-NS5A 4d clone encoding A1671S, T1785V, and D2411G was viable in Huh7.5 cells, with efficient growth after inclusion of 10 additional substitutions [4d(C5A)-13m]. The efficacies of NS3/4A protease- and NS5A- inhibitors against genotypes 4a and 4d were similar, except for ledipasvir, which is less potent against 4d. Compared to 4a, the 4d(C5A)-13m virus was more sensitive to neutralizing monoclonal antibodies AR3A and AR5A, as well as 4a and 4d patient plasma antibodies. In conclusion, we developed the first genotype 4d infectious culture system enabling DAA efficacy testing and antibody neutralization assessment critical to optimization of DAA treatments in the clinic and for vaccine design to combat the HCV epidemic.
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