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

• Published in: PLoS pathogens Vol. 19; no. 1; p. e1011107
• Main Authors: Jenks, Jennifer A., Amin, Sharmi, Sponholtz, Madeline R., Kumar, Amit, Wrapp, Daniel, Venkatayogi, Sravani, Tu, Joshua J., Karthigeyan, Krithika, Valencia, Sarah M., Connors, Megan, Harnois, Melissa J., Hora, Bhavna, Rochat, Eric, McLellan, Jason S., Wiehe, Kevin, Permar, Sallie R.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.01.2023; Public Library of Science (PLoS)
• Subjects: Amino acids; Antibodies; Antibodies, Neutralizing - genetics; Antibodies, Neutralizing - immunology; Antibodies, Viral - genetics; Antibodies, Viral - immunology; Antigens; BASIC BIOLOGICAL SCIENCES; Biology and Life Sciences; Care and treatment; Cell receptors; Cloning; Congenital diseases; Cytomegalovirus; Cytomegalovirus - genetics; Cytomegalovirus - immunology; Cytomegalovirus infections; Cytomegalovirus Infections - genetics; Cytomegalovirus Infections - immunology; Cytomegalovirus Vaccines - therapeutic use; Development and progression; Epitopes; Gene mutations; Genealogy; Genetic aspects; Glycoprotein B; Glycoproteins; Health aspects; Hearing loss; Host-virus relationships; Humans; Immune response; Infections; Lymphocytes B; Medicine and Health Sciences; Microbiology; Mutation; Neutralization; Neutralizing; Parasitology; Phylogenetics; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; Somatic hypermutation; Vaccines; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology; Virology; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011107

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.