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A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus.

Publication ,  Journal Article
Jenks, JA; Amin, S; Sponholtz, MR; Kumar, A; Wrapp, D; Venkatayogi, S; Tu, JJ; Karthigeyan, K; Valencia, SM; Connors, M; Harnois, MJ; Hora, B ...
Published in: PLoS pathogens
January 2023

Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines.

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Published In

PLoS pathogens

DOI

EISSN

1553-7374

ISSN

1553-7366

Publication Date

January 2023

Volume

19

Issue

1

Start / End Page

e1011107

Related Subject Headings

  • Virology
  • Viral Envelope Proteins
  • Receptors, Antigen, B-Cell
  • Mutation
  • Humans
  • Cytomegalovirus Vaccines
  • Cytomegalovirus Infections
  • Cytomegalovirus
  • Antibodies, Viral
  • Antibodies, Neutralizing
 

Citation

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Jenks, J. A., Amin, S., Sponholtz, M. R., Kumar, A., Wrapp, D., Venkatayogi, S., … Permar, S. R. (2023). A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus. PLoS Pathogens, 19(1), e1011107. https://doi.org/10.1371/journal.ppat.1011107
Jenks, Jennifer A., Sharmi Amin, Madeline R. Sponholtz, Amit Kumar, Daniel Wrapp, Sravani Venkatayogi, Joshua J. Tu, et al. “A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus.PLoS Pathogens 19, no. 1 (January 2023): e1011107. https://doi.org/10.1371/journal.ppat.1011107.
Jenks JA, Amin S, Sponholtz MR, Kumar A, Wrapp D, Venkatayogi S, et al. A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus. PLoS pathogens. 2023 Jan;19(1):e1011107.
Jenks, Jennifer A., et al. “A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus.PLoS Pathogens, vol. 19, no. 1, Jan. 2023, p. e1011107. Epmc, doi:10.1371/journal.ppat.1011107.
Jenks JA, Amin S, Sponholtz MR, Kumar A, Wrapp D, Venkatayogi S, Tu JJ, Karthigeyan K, Valencia SM, Connors M, Harnois MJ, Hora B, Rochat E, McLellan JS, Wiehe K, Permar SR. A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus. PLoS pathogens. 2023 Jan;19(1):e1011107.

Published In

PLoS pathogens

DOI

EISSN

1553-7374

ISSN

1553-7366

Publication Date

January 2023

Volume

19

Issue

1

Start / End Page

e1011107

Related Subject Headings

  • Virology
  • Viral Envelope Proteins
  • Receptors, Antigen, B-Cell
  • Mutation
  • Humans
  • Cytomegalovirus Vaccines
  • Cytomegalovirus Infections
  • Cytomegalovirus
  • Antibodies, Viral
  • Antibodies, Neutralizing