A Recombinant Hepatitis C Virus Genotype 1a E1/E2 Envelope Glycoprotein Vaccine Elicits Antibodies That Differentially Neutralize Closely Related 2a Strains through Interactions of the N-Terminal Hypervariable Region 1 of E2 with Scavenger Receptor B1
| Autor: | Janelle Johnson, Darren Hockman, John Lok Man Law, Michael Houghton, D. Lorne Tyrrell, Jason Wong, Holly Freedman, Michael R. Beard, Jianqi He, Thomas F. Baumert, Chao Chen, Michael Logan, Nicholas S. Eyre |
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| Přispěvatelé: | Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Alberta, University of Adelaide, Les Hôpitaux Universitaires de Strasbourg (HUS), univOAK, Archive ouverte |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
hepatitis C virus
Aucun Hepacivirus medicine.disease_cause Neutralization genotype 2a Epitopes 0302 clinical medicine scavenger receptor B1 Viral Envelope Proteins vaccine Genotype chemistry.chemical_classification Receptors Scavenger [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology 0303 health sciences Vaccines Synthetic isolate-specific biology Antibodies Monoclonal Scavenger Receptors Class B Hepatitis C 3. Good health [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology 030211 gastroenterology & hepatology Antibody Viral Hepatitis Vaccines Hepatitis C virus Immunology Sciences du Vivant [q-bio]/Médecine humaine et pathologie Microbiology Virus Cell Line 03 medical and health sciences [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology Neutralization Tests Virology Vaccines and Antiviral Agents medicine Humans neutralizing antibodies 030304 developmental biology Antiserum Hepatitis C Antibodies Antibodies Neutralizing Complementarity Determining Regions digestive system diseases Hypervariable region chemistry hypervariable region 1 Insect Science biology.protein Hepatitis C Antigens [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology Glycoprotein [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology |
| Zdroj: | Journal of Virology Journal of Virology, American Society for Microbiology, 2019, 93 (22), ⟨10.1128/JVI.00810-19⟩ Journal of Virology, 2019, 93 (22), pp.e00810-19. ⟨10.1128/JVI.00810-19⟩ |
| ISSN: | 0022-538X 1098-5514 |
| Popis: | A vaccine is still urgently needed to overcome the hepatitis C virus (HCV) epidemic. It is estimated that 1.75 million new HCV infections occur each year, many of which will go undiagnosed and untreated. Untreated HCV can lead to continued spread of the disease, progressive liver fibrosis, cirrhosis, and eventually, end-stage liver disease and/or hepatocellular carcinoma (HCC). Previously, our 1a E1/E2 glycoprotein vaccine was shown to elicit broadly cross-neutralizing antibodies; however, there remains variation in the effectiveness of these antibodies against different HCV genotypes. In this study, we investigated determinants of differential neutralization sensitivity between two highly related genotype 2a isolates, J6 and JFH-1. Our data indicate that the HVR1 region determines neutralization sensitivity to vaccine antisera through modulation of sensitivity to antibodies and interactions with SR-B1. Our results provide additional insight into optimizing a broadly neutralizing HCV vaccine. The global health burden for hepatitis C virus (HCV) remains high, despite available effective treatments. To eliminate HCV, a prophylactic vaccine is needed. One major challenge in the development of a vaccine is the genetic diversity of the virus, with 7 major genotypes and many subtypes. A global vaccine must be effective against all HCV genotypes. Our previous data showed that the 1a E1/E2 glycoprotein vaccine component elicits broad cross-neutralizing antibodies in humans and animals. However, some variation is seen in the effectiveness of these antibodies to neutralize different HCV genotypes and isolates. Of interest was the differences in neutralizing activity against two closely related isolates of HCV genotype 2a, the J6 and JFH-1 strains. Using site-directed mutagenesis to generate chimeric viruses between the J6 and JFH-1 strains, we found that variant amino acids within the core E2 glycoprotein domain of these two HCV genotype 2a viruses do not influence isolate-specific neutralization. Further analysis revealed that the N-terminal hypervariable region 1 (HVR1) of the E2 protein determines the sensitivity of isolate-specific neutralization, and the HVR1 of the resistant J6 strain binds scavenger receptor class-B type-1 (SR-B1), while the sensitive JFH-1 strain does not. Our data provide new information on mechanisms of isolate-specific neutralization to facilitate the optimization of a much-needed HCV vaccine. IMPORTANCE A vaccine is still urgently needed to overcome the hepatitis C virus (HCV) epidemic. It is estimated that 1.75 million new HCV infections occur each year, many of which will go undiagnosed and untreated. Untreated HCV can lead to continued spread of the disease, progressive liver fibrosis, cirrhosis, and eventually, end-stage liver disease and/or hepatocellular carcinoma (HCC). Previously, our 1a E1/E2 glycoprotein vaccine was shown to elicit broadly cross-neutralizing antibodies; however, there remains variation in the effectiveness of these antibodies against different HCV genotypes. In this study, we investigated determinants of differential neutralization sensitivity between two highly related genotype 2a isolates, J6 and JFH-1. Our data indicate that the HVR1 region determines neutralization sensitivity to vaccine antisera through modulation of sensitivity to antibodies and interactions with SR-B1. Our results provide additional insight into optimizing a broadly neutralizing HCV vaccine. |
| Databáze: | OpenAIRE |
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