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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. 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.

CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, F-69007, Lyon, France.

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, 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 Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

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. The standardized criteria defined in this paper, amino acid positions and property classes, will be useful to study the mutations and allele polymorphisms, to establish correlations between amino acids in the IG and TR protein three-dimensional structures and to extract new knowledge from V-like domains of chains, other than IG and TR, belonging to the immunoglobulin superfamily.To achieve global elimination of hepatitis C virus (HCV), an effective cross-genotype vaccine is needed.

They provide a characterization of the amino acid properties at each framework position of the expressed IG V-REGIONs, and a visualization of the resemblances and differences between heavy and light, and between kappa and lambda sequences. Results of the analyses are shown as standardized two-dimensional representations, designated as IMGT Colliers de Perles statistical profiles. Two statistical methods (correspondence analysis and hierarchic classification) were used to analyze the 237 framework positions (80 for IGHV, 79 for IGKV, 78 for IGLV), for three properties (hydropathy, volume and chemical characteristics) of the 20 common amino acids. The framework amino acid positions of 2474 V-REGIONs (1360 IGHV, 585 IGKV, 529 IGLV) were numbered according to the IMGT unique numbering. In order to define the IMGT criteria necessary for standardized statistical analyses, the sequences of the IG variable regions (V-REGIONs) from productively rearranged human IG heavy (IGH) and IG light kappa (IGK) and lambda (IGL) chains were extracted from IMGT/LIGM-DB. IMGT comprises IMGT/LIGM-DB, the comprehensive database of IG and TR sequences from human and other vertebrates (76 846 sequences in September 2003). IMGT, the international ImMunoGeneTics information system(R) () is a high-quality integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates.