Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance

Justin Bailey, Andrew I. Flyak, Valerie J. Cohen, Hui Li, Lisa N. Wasilewski, Anna E. Snider, Shuyi Wang, Gerald H. Learn, Nurgun Kose, Leah Loerinc, Rebecca Lampley, Andrea Cox, Jennifer M. Pfaff, Benjamin J. Doranz, George M. Shaw, Stuart Campbell Ray, James E. Crowe

Research output: Contribution to journalArticle

Abstract

Here, we report the isolation of broadly neutralizing mAbs (bNAbs) from persons with broadly neutralizing serum who spontaneously cleared hepatitis C virus (HCV) infection. We found that bNAbs from two donors bound the same epitope and were encoded by the same germline heavy chain variable gene segment. Remarkably, these bNAbs were encoded by antibody variable genes with sparse somatic mutations. For one of the most potent bNAbs, these somatic mutations were critical for antibody neutralizing breadth and for binding to autologous envelope variants circulating late in infection. However, somatic mutations were not necessary for binding of the bNAb unmutated ancestor to envelope proteins of early autologous transmitted/founder viruses. This study identifies a public B cell clonotype favoring early recognition of a conserved HCV epitope, proving that anti-HCV bNAbs can achieve substantial neutralizing breadth with relatively few somatic mutations, and identifies HCV envelope variants that favored selection and maturation of an anti-HCV bNAb in vivo. These data provide insight into the molecular mechanisms of immune-mediated clearance of HCV infection and present a roadmap to guide development of a vaccine capable of stimulating anti-HCV bNAbs with a physiologic number of somatic mutations characteristic of vaccine responses.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number9
DOIs
StatePublished - May 4 2017

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Neutralizing Antibodies
Hepacivirus
Mutation
Virus Diseases
Epitopes
Vaccines
Genes
B-Lymphocytes
Viruses
Antibodies
Infection
Serum
Proteins

Keywords

  • Infectious disease

Cite this

Bailey, J., Flyak, A. I., Cohen, V. J., Li, H., Wasilewski, L. N., Snider, A. E., ... Crowe, J. E. (2017). Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance. JCI insight, 2(9). https://doi.org/10.1172/jci.insight.92872

Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance. / Bailey, Justin; Flyak, Andrew I.; Cohen, Valerie J.; Li, Hui; Wasilewski, Lisa N.; Snider, Anna E.; Wang, Shuyi; Learn, Gerald H.; Kose, Nurgun; Loerinc, Leah; Lampley, Rebecca; Cox, Andrea; Pfaff, Jennifer M.; Doranz, Benjamin J.; Shaw, George M.; Ray, Stuart Campbell; Crowe, James E.

In: JCI insight, Vol. 2, No. 9, 04.05.2017.

Research output: Contribution to journalArticle

Bailey, J, Flyak, AI, Cohen, VJ, Li, H, Wasilewski, LN, Snider, AE, Wang, S, Learn, GH, Kose, N, Loerinc, L, Lampley, R, Cox, A, Pfaff, JM, Doranz, BJ, Shaw, GM, Ray, SC & Crowe, JE 2017, 'Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance', JCI insight, vol. 2, no. 9. https://doi.org/10.1172/jci.insight.92872
Bailey, Justin ; Flyak, Andrew I. ; Cohen, Valerie J. ; Li, Hui ; Wasilewski, Lisa N. ; Snider, Anna E. ; Wang, Shuyi ; Learn, Gerald H. ; Kose, Nurgun ; Loerinc, Leah ; Lampley, Rebecca ; Cox, Andrea ; Pfaff, Jennifer M. ; Doranz, Benjamin J. ; Shaw, George M. ; Ray, Stuart Campbell ; Crowe, James E. / Broadly neutralizing antibodies with few somatic mutations and hepatitis C virus clearance. In: JCI insight. 2017 ; Vol. 2, No. 9.
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