![]() ![]() This E2 B structure may represent another conformational state in the viral entry process that is susceptible to antibody neutralization and thus provide a new target for rational vaccine development. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. ![]() CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, F-69007, Lyon, France.Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.(ANL), Argonne, IL (United States) Sponsoring Org.: USDOE Office of Science (SC), Basic Energy Sciences (BES) OSTI Identifier: 1643153 Alternate Identifier(s): OSTI ID: 1816246 Grant/Contract Number: AC02-06CH11357 Resource Type: Published Article Journal Name: Science Advances Additional Journal Information: Journal Name: Science Advances Journal Volume: 6 Journal Issue: 30 Journal ID: ISSN 2375-2548 Publisher: American Association for the Advancement of Science (AAAS) Country of Publication: United States Language: English Subject: 59 BASIC BIOLOGICAL =, Publication Date: Fri Jul 24 00:00: Research Org.: Argonne National Lab. Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell–based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and more » 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes. « lessĮlicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. ![]() Six of the mAbs recognize the conserved E2 antigenic site 412–423 (AS412) and cross-neutralize diverse HCV genotypes. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Intriguingly, the anti-HCV activity of one antibody lineage is associated with maturation of the light chain (LC), whereas the other lineage is more » dependent on heavy-chain (HC) maturation. Crystal structures of GL precursors of the LC-dependent lineage in complex with AS412 offer critical insights into the maturation process of bnAbs to HCV, thus providing a scientific foundation for utilizing the mouse model to study AS412-targeting vaccine candidates. Hepatitis C virus (HCV) is a positive-strand RNA virus within the Flaviviridae family. The viral “spike” of HCV is formed by two envelope glycoproteins, E1 and E2, which together mediate viral entry by engaging host receptors and undergoing conformational changes to facilitate membrane fusion. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |