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Structure of Hepatitis C Virus Envelope Glycoprotein E2mc3-v1 redesigned core from genotype 1a bound to broadly neutralizing antibody AR3CStructure of Hepatitis C Virus Envelope Glycoprotein E2mc3-v1 redesigned core from genotype 1a bound to broadly neutralizing antibody AR3C
Structural highlights
Publication Abstract from PubMedHepatitis 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 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. Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines.,He L, Tzarum N, Lin X, Shapero B, Sou C, Mann CJ, Stano A, Zhang L, Nagy K, Giang E, Law M, Wilson IA, Zhu J Sci Adv. 2020 Apr 15;6(16):eaaz6225. doi: 10.1126/sciadv.aaz6225. eCollection, 2020 Apr. PMID:32494617[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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