Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors

Aleman, Fernando; Tzarum, Netanel; Kong, Leopold; Nagy, Kenna; Zhu, Jiang; Wilson, Ian A.; Law, Mansun

doi:10.1073/pnas.1802378115

Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors

Journal Article · Thu Jun 28 00:00:00 EDT 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1802378115· OSTI ID:1497190

^[1]; Tzarum, Netanel ^[1]; Kong, Leopold ^[1]; Nagy, Kenna ^[1]; Zhu, Jiang ^[1]; Wilson, Ian A. ^[1]; Law, Mansun ^[1]

The Scripps Research Inst., La Jolla, CA (United States)

Elicitation 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 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Center for Research Resources; National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1497190

Report Number(s):: 29637

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 29 Vol. 115; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
E1E2 glycoproteins
HCV vaccine
antibody germline precursors
broadly neutralizing antibodies
hepatitis C Virus

Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors

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References (47)

Cited By (2)

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