Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies
Abstract
The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505. N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategymore »
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- Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery
- Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
- Dept. of Health and Human Services, Research Triangle Park, NC (United States). National Institutes of Health. National Institute of Environmental Health Sciences. Genome Integrity and Structural Biology Lab.
- National Inst. of Health (NIH), Bethesda, MD (United States). National Institute of Allergy and Infectious Diseases. Vaccine Research Center
- Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.; Duke Univ., Durham, NC (United States). Medical Center. Dept. of Medicine
- Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery; Rory Henderson Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
- Univ. of Oxford (United Kingdom). The Sir William Dunn School of Pathology
- Boston Univ., MA (United States). School of Medicine. Dept. of Microbiology
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics
- Duke Univ., Durham, NC (United States). Medical Center. Dept. of Surgery; Rory Henderson Duke Univ., Durham, NC (United States). Medical Center. Duke Human Vaccine Inst.
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
- OSTI Identifier:
- 1627919
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Pathogens
- Additional Journal Information:
- Journal Volume: 15; Journal Issue: 9; Journal ID: ISSN 1553-7374
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; Microbiology; Parasitology; Virology
Citation Formats
LaBranche, Celia C., Henderson, Rory, Hsu, Allen, Behrens, Shay, Chen, Xuejun, Zhou, Tongqing, Wiehe, Kevin, Saunders, Kevin O., Alam, S. Munir, Bonsignori, Mattia, Borgnia, Mario J., Sattentau, Quentin J., Eaton, Amanda, Greene, Kelli, Gao, Hongmei, Liao, Hua-Xin, Williams, Wilton B., Peacock, James, Tang, Haili, Perez, Lautaro G., Edwards, Robert J., Kepler, Thomas B., Korber, Bette T., Kwong, Peter D., Mascola, John R., Acharya, Priyamvada, Haynes, Barton F., and Montefiori, David C. Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. United States: N. p., 2019.
Web. doi:10.1371/journal.ppat.1008026.
LaBranche, Celia C., Henderson, Rory, Hsu, Allen, Behrens, Shay, Chen, Xuejun, Zhou, Tongqing, Wiehe, Kevin, Saunders, Kevin O., Alam, S. Munir, Bonsignori, Mattia, Borgnia, Mario J., Sattentau, Quentin J., Eaton, Amanda, Greene, Kelli, Gao, Hongmei, Liao, Hua-Xin, Williams, Wilton B., Peacock, James, Tang, Haili, Perez, Lautaro G., Edwards, Robert J., Kepler, Thomas B., Korber, Bette T., Kwong, Peter D., Mascola, John R., Acharya, Priyamvada, Haynes, Barton F., & Montefiori, David C. Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies. United States. https://doi.org/10.1371/journal.ppat.1008026
LaBranche, Celia C., Henderson, Rory, Hsu, Allen, Behrens, Shay, Chen, Xuejun, Zhou, Tongqing, Wiehe, Kevin, Saunders, Kevin O., Alam, S. Munir, Bonsignori, Mattia, Borgnia, Mario J., Sattentau, Quentin J., Eaton, Amanda, Greene, Kelli, Gao, Hongmei, Liao, Hua-Xin, Williams, Wilton B., Peacock, James, Tang, Haili, Perez, Lautaro G., Edwards, Robert J., Kepler, Thomas B., Korber, Bette T., Kwong, Peter D., Mascola, John R., Acharya, Priyamvada, Haynes, Barton F., and Montefiori, David C. Tue .
"Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies". United States. https://doi.org/10.1371/journal.ppat.1008026. https://www.osti.gov/servlets/purl/1627919.
@article{osti_1627919,
title = {Neutralization-guided design of HIV-1 envelope trimers with high affinity for the unmutated common ancestor of CH235 lineage CD4bs broadly neutralizing antibodies},
author = {LaBranche, Celia C. and Henderson, Rory and Hsu, Allen and Behrens, Shay and Chen, Xuejun and Zhou, Tongqing and Wiehe, Kevin and Saunders, Kevin O. and Alam, S. Munir and Bonsignori, Mattia and Borgnia, Mario J. and Sattentau, Quentin J. and Eaton, Amanda and Greene, Kelli and Gao, Hongmei and Liao, Hua-Xin and Williams, Wilton B. and Peacock, James and Tang, Haili and Perez, Lautaro G. and Edwards, Robert J. and Kepler, Thomas B. and Korber, Bette T. and Kwong, Peter D. and Mascola, John R. and Acharya, Priyamvada and Haynes, Barton F. and Montefiori, David C.},
abstractNote = {The CD4 binding site (CD4bs) of the HIV-1 envelope glycoprotein is susceptible to multiple lineages of broadly neutralizing antibodies (bnAbs) that are attractive to elicit with vaccines. The CH235 lineage (VH1-46) of CD4bs bnAbs is particularly attractive because the most mature members neutralize 90% of circulating strains, do not possess long HCDR3 regions, and do not contain insertions and deletions that may be difficult to induce. We used virus neutralization to measure the interaction of CH235 unmutated common ancestor (CH235 UCA) with functional Env trimers on infectious virions to guide immunogen design for this bnAb lineage. Two Env mutations were identified, one in loop D (N279K) and another in V5 (G458Y), that acted synergistically to render autologous CH505 transmitted/founder virus susceptible to neutralization by CH235 UCA. Man5-enriched N-glycans provided additional synergy for neutralization. CH235 UCA bound with nanomolar affinity to corresponding soluble native-like Env trimers as candidate immunogens. A cryo-EM structure of CH235 UCA bound to Man5-enriched CH505. N279K.G458Y.SOSIP.664 revealed interactions of the antibody light chain complementarity determining region 3 (CDR L3) with the engineered Env loops D and V5. These results demonstrate that virus neutralization can directly inform vaccine design and suggest a germline targeting and reverse engineering strategy to initiate and mature the CH235 bnAb lineage.},
doi = {10.1371/journal.ppat.1008026},
journal = {PLoS Pathogens},
number = 9,
volume = 15,
place = {United States},
year = {Tue Sep 17 00:00:00 EDT 2019},
month = {Tue Sep 17 00:00:00 EDT 2019}
}
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