This content will become publicly available on August 3, 2020
Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses
Abstract
Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.
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- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
- International AIDS Vaccine Initiative, Neutralizing Antibody Center, Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
- Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
- Publication Date:
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1573531
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- Journal of Experimental Medicine
- Additional Journal Information:
- Journal Name: Journal of Experimental Medicine; Journal ID: ISSN 0022-1007
- Publisher:
- Rockefeller University Press
- Country of Publication:
- United States
- Language:
- English
Citation Formats
Phad, Ganesh E., Pushparaj, Pradeepa, Tran, Karen, Dubrovskaya, Viktoriya, Àdori, Monika, Martinez-Murillo, Paola, Vázquez Bernat, Néstor, Singh, Suruchi, Dionne, Gilman, O’Dell, Sijy, Bhullar, Komal, Narang, Sanjana, Sorini, Chiara, Villablanca, Eduardo J., Sundling, Christopher, Murrell, Benjamin, Mascola, John R., Shapiro, Lawrence, Pancera, Marie, Martin, Marcel, Corcoran, Martin, Wyatt, Richard T., and Karlsson Hedestam, Gunilla B. Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses. United States: N. p., 2019.
Web. doi:10.1084/jem.20191155.
Phad, Ganesh E., Pushparaj, Pradeepa, Tran, Karen, Dubrovskaya, Viktoriya, Àdori, Monika, Martinez-Murillo, Paola, Vázquez Bernat, Néstor, Singh, Suruchi, Dionne, Gilman, O’Dell, Sijy, Bhullar, Komal, Narang, Sanjana, Sorini, Chiara, Villablanca, Eduardo J., Sundling, Christopher, Murrell, Benjamin, Mascola, John R., Shapiro, Lawrence, Pancera, Marie, Martin, Marcel, Corcoran, Martin, Wyatt, Richard T., & Karlsson Hedestam, Gunilla B. Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses. United States. doi:10.1084/jem.20191155.
Phad, Ganesh E., Pushparaj, Pradeepa, Tran, Karen, Dubrovskaya, Viktoriya, Àdori, Monika, Martinez-Murillo, Paola, Vázquez Bernat, Néstor, Singh, Suruchi, Dionne, Gilman, O’Dell, Sijy, Bhullar, Komal, Narang, Sanjana, Sorini, Chiara, Villablanca, Eduardo J., Sundling, Christopher, Murrell, Benjamin, Mascola, John R., Shapiro, Lawrence, Pancera, Marie, Martin, Marcel, Corcoran, Martin, Wyatt, Richard T., and Karlsson Hedestam, Gunilla B. Fri .
"Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses". United States. doi:10.1084/jem.20191155.
@article{osti_1573531,
title = {Extensive dissemination and intraclonal maturation of HIV Env vaccine-induced B cell responses},
author = {Phad, Ganesh E. and Pushparaj, Pradeepa and Tran, Karen and Dubrovskaya, Viktoriya and Àdori, Monika and Martinez-Murillo, Paola and Vázquez Bernat, Néstor and Singh, Suruchi and Dionne, Gilman and O’Dell, Sijy and Bhullar, Komal and Narang, Sanjana and Sorini, Chiara and Villablanca, Eduardo J. and Sundling, Christopher and Murrell, Benjamin and Mascola, John R. and Shapiro, Lawrence and Pancera, Marie and Martin, Marcel and Corcoran, Martin and Wyatt, Richard T. and Karlsson Hedestam, Gunilla B.},
abstractNote = {Well-ordered HIV-1 envelope glycoprotein (Env) trimers are prioritized for clinical evaluation, and there is a need for an improved understanding about how elicited B cell responses evolve following immunization. To accomplish this, we prime-boosted rhesus macaques with clade C NFL trimers and identified 180 unique Ab lineages from ∼1,000 single-sorted Env-specific memory B cells. We traced all lineages in high-throughput heavy chain (HC) repertoire (Rep-seq) data generated from multiple immune compartments and time points and expressed several as monoclonal Abs (mAbs). Our results revealed broad dissemination and high levels of somatic hypermutation (SHM) of most lineages, including tier 2 virus neutralizing lineages, following boosting. SHM was highest in the Ab complementarity determining regions (CDRs) but also surprisingly high in the framework regions (FRs), especially FR3. Our results demonstrate the capacity of the immune system to affinity-mature large numbers of Env-specific B cell lineages simultaneously, supporting the use of regimens consisting of repeated boosts to improve each Ab, even those belonging to less expanded lineages.},
doi = {10.1084/jem.20191155},
journal = {Journal of Experimental Medicine},
number = ,
volume = ,
place = {United States},
year = {2019},
month = {11}
}
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DOI: 10.1084/jem.20191155
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