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. Hepatitis C virus (HCV) is a positive-strand RNA virus within the Flaviviridae family. 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. 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. Immunogenetic and structural analysis revealed that the antibodies originated from two different germline (GL) precursors and bind AS412 in a β-hairpin conformation. Six of the mAbs recognize the conserved E2 antigenic site 412–423 (AS412) and cross-neutralize diverse HCV genotypes. Here, we studied a panel of monoclonal antibodies (mAbs) from mice immunized with the hepatitis C virus (HCV) envelope glycoproteins E1E2. « lessĮlicitation of broadly neutralizing antibodies (bnAbs) is a leading strategy in rational vaccine design against antigenically diverse pathogens. 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. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. We then displayed these E2 cores on 24- and more » 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced 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 redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Here, we present a comprehensive strategy for B cell–based HCV vaccine development through E2 optimization and nanoparticle display. Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). (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.
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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. In this conformation, the E2 front-layer region is displaced upon antibody binding, exposing residues in the back layer for direct antibody interaction. Here, a previously unknown conformation (B) of the neutralizing face is revealed in crystal structures of two of four additional E2–V H1-69 nAb complexes. Many nAbs bind to the “neutralizing face” on E2, including several broadly nAbs encoded by the V H1-69 germline gene family that bind to a similar conformation (A) of this face. E2 is structurally flexible and functions in engaging host receptors. The HCV envelope glycoprotein E2 is the main target for neutralizing antibodies (nAbs), which aid in HCV clearance and protection. To achieve global elimination of hepatitis C virus (HCV), an effective cross-genotype vaccine is needed.