Relation between viral fitness and immune escape within the hepatitis C virus protease
| Autor: | Mats Alheim, Artur Kaul, Peter Liljeström, Ralf Bartenschlager, Gustaf Ahlén, Christina Barnfield, Lars Frelin, Jonas Söderholm, David R. Milich, Matti Sällberg, Ola Weiland |
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| Rok vydání: | 2006 |
| Předmět: |
Adult
Cytotoxicity Immunologic Male Proteases Genes Viral viruses Hepatitis C virus Epitopes T-Lymphocyte Mice Transgenic Hepacivirus Viral Nonstructural Proteins Biology Virus Replication medicine.disease_cause Epitope Virus Hepatitis Mice HLA-A2 Antigen Immune Tolerance medicine Animals Humans NS3 Immunodominant Epitopes Gastroenterology Genetic Variation Hepatitis C Chronic Middle Aged Hepatitis C Virology Peptide Fragments Mice Inbred C57BL NS2-3 protease CTL Viral replication Acute Disease Mutation Immunology RNA Viral Female T-Lymphocytes Cytotoxic |
| Zdroj: | Gut. 55:266-274 |
| ISSN: | 0017-5749 |
| Popis: | Background: The hepatitis C virus (HCV) mutates within human leucocyte antigen (HLA) class I restricted immunodominant epitopes of the non-structural (NS) 3/4A protease to escape cytotoxic T lymphocyte (CTL) recognition and promote viral persistence. However, variability is not unlimited, and sometimes almost absent, and factors that restrict viral variability have not been defined experimentally. Aims: We wished to explore whether the variability of the immunodominant CTL epitope at residues 1073–1081 of the NS3 protease was limited by viral fitness. Patients: Venous blood was obtained from six patients (four HLA-A2+) with chronic HCV infection and from one HLA-A2+ patient with acute HCV infection. Methods: NS3/4A genes were amplified from serum, cloned in a eukaryotic expression plasmid, sequenced, and expressed. CTL recognition of naturally occurring and artificially introduced escape mutations in HLA-A2-restricted NS3 epitopes were determined using CTLs from human blood and genetically immunised HLA-A2-transgenic mice. HCV replicons were used to test the effect of escape mutations on HCV protease activity and RNA replication. Results: Sequence analysis of NS3/4A confirmed low genetic variability. The major viral species had functional proteases with 1073–1081 epitopes that were generally recognised by cross reactive human and murine HLA-A2 restricted CTLs. Introduction of mutations at five positions of the 1073–1081 epitope prevented CTL recognition but three of these reduced protease activity and RNA replication. Conclusions: Viral fitness can indeed limit the variability of HCV within immunological epitopes. This helps to explain why certain immunological escape variants never appear as a major viral species in infected humans. |
| Databáze: | OpenAIRE |
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