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Title: Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody

Abstract

Here, we report that antibodies with ontogenies from V H1-2 or V H1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. We define with longitudinal sampling from time-of-infection the development of a V H1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled V H1-2. Lastly, we integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.

Authors:
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Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1350149
Alternate Identifier(s):
OSTI ID: 1259969; OSTI ID: 1324843
Report Number(s):
LA-UR-15-29619
Journal ID: ISSN 0092-8674; S0092867416301246; PII: S0092867416301246
Grant/Contract Number:  
W-31-109-Eng-38; AC52-06NA25396; UM1 AI100645; UM1 AI100663; P01-AI104722
Resource Type:
Published Article
Journal Name:
Cell
Additional Journal Information:
Journal Name: Cell Journal Volume: 165 Journal Issue: 2; Journal ID: ISSN 0092-8674
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Bonsignori, Mattia, Zhou, Tongqing, Sheng, Zizhang, Chen, Lei, Gao, Feng, Joyce, M. Gordon, Ozorowski, Gabriel, Chuang, Gwo-Yu, Schramm, Chaim A., Wiehe, Kevin, Alam, S. Munir, Bradley, Todd, Gladden, Morgan A., Hwang, Kwan-Ki, Iyengar, Sheelah, Kumar, Amit, Lu, Xiaozhi, Luo, Kan, Mangiapani, Michael C., Parks, Robert J., Song, Hongshuo, Acharya, Priyamvada, Bailer, Robert T., Cao, Allen, Druz, Aliaksandr, Georgiev, Ivelin S., Kwon, Young D., Louder, Mark K., Zhang, Baoshan, Zheng, Anqi, Hill, Brenna J., Kong, Rui, Soto, Cinque, Mullikin, James C., Douek, Daniel C., Montefiori, David C., Moody, Michael A., Shaw, George M., Hahn, Beatrice H., Kelsoe, Garnett, Hraber, Peter T., Korber, Bette T., Boyd, Scott D., Fire, Andrew Z., Kepler, Thomas B., Shapiro, Lawrence, Ward, Andrew B., Mascola, John R., Liao, Hua-Xin, Kwong, Peter D., and Haynes, Barton F. Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. United States: N. p., 2016. Web. doi:10.1016/j.cell.2016.02.022.
Bonsignori, Mattia, Zhou, Tongqing, Sheng, Zizhang, Chen, Lei, Gao, Feng, Joyce, M. Gordon, Ozorowski, Gabriel, Chuang, Gwo-Yu, Schramm, Chaim A., Wiehe, Kevin, Alam, S. Munir, Bradley, Todd, Gladden, Morgan A., Hwang, Kwan-Ki, Iyengar, Sheelah, Kumar, Amit, Lu, Xiaozhi, Luo, Kan, Mangiapani, Michael C., Parks, Robert J., Song, Hongshuo, Acharya, Priyamvada, Bailer, Robert T., Cao, Allen, Druz, Aliaksandr, Georgiev, Ivelin S., Kwon, Young D., Louder, Mark K., Zhang, Baoshan, Zheng, Anqi, Hill, Brenna J., Kong, Rui, Soto, Cinque, Mullikin, James C., Douek, Daniel C., Montefiori, David C., Moody, Michael A., Shaw, George M., Hahn, Beatrice H., Kelsoe, Garnett, Hraber, Peter T., Korber, Bette T., Boyd, Scott D., Fire, Andrew Z., Kepler, Thomas B., Shapiro, Lawrence, Ward, Andrew B., Mascola, John R., Liao, Hua-Xin, Kwong, Peter D., & Haynes, Barton F. Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. United States. doi:10.1016/j.cell.2016.02.022.
Bonsignori, Mattia, Zhou, Tongqing, Sheng, Zizhang, Chen, Lei, Gao, Feng, Joyce, M. Gordon, Ozorowski, Gabriel, Chuang, Gwo-Yu, Schramm, Chaim A., Wiehe, Kevin, Alam, S. Munir, Bradley, Todd, Gladden, Morgan A., Hwang, Kwan-Ki, Iyengar, Sheelah, Kumar, Amit, Lu, Xiaozhi, Luo, Kan, Mangiapani, Michael C., Parks, Robert J., Song, Hongshuo, Acharya, Priyamvada, Bailer, Robert T., Cao, Allen, Druz, Aliaksandr, Georgiev, Ivelin S., Kwon, Young D., Louder, Mark K., Zhang, Baoshan, Zheng, Anqi, Hill, Brenna J., Kong, Rui, Soto, Cinque, Mullikin, James C., Douek, Daniel C., Montefiori, David C., Moody, Michael A., Shaw, George M., Hahn, Beatrice H., Kelsoe, Garnett, Hraber, Peter T., Korber, Bette T., Boyd, Scott D., Fire, Andrew Z., Kepler, Thomas B., Shapiro, Lawrence, Ward, Andrew B., Mascola, John R., Liao, Hua-Xin, Kwong, Peter D., and Haynes, Barton F. Fri . "Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody". United States. doi:10.1016/j.cell.2016.02.022.
@article{osti_1350149,
title = {Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody},
author = {Bonsignori, Mattia and Zhou, Tongqing and Sheng, Zizhang and Chen, Lei and Gao, Feng and Joyce, M. Gordon and Ozorowski, Gabriel and Chuang, Gwo-Yu and Schramm, Chaim A. and Wiehe, Kevin and Alam, S. Munir and Bradley, Todd and Gladden, Morgan A. and Hwang, Kwan-Ki and Iyengar, Sheelah and Kumar, Amit and Lu, Xiaozhi and Luo, Kan and Mangiapani, Michael C. and Parks, Robert J. and Song, Hongshuo and Acharya, Priyamvada and Bailer, Robert T. and Cao, Allen and Druz, Aliaksandr and Georgiev, Ivelin S. and Kwon, Young D. and Louder, Mark K. and Zhang, Baoshan and Zheng, Anqi and Hill, Brenna J. and Kong, Rui and Soto, Cinque and Mullikin, James C. and Douek, Daniel C. and Montefiori, David C. and Moody, Michael A. and Shaw, George M. and Hahn, Beatrice H. and Kelsoe, Garnett and Hraber, Peter T. and Korber, Bette T. and Boyd, Scott D. and Fire, Andrew Z. and Kepler, Thomas B. and Shapiro, Lawrence and Ward, Andrew B. and Mascola, John R. and Liao, Hua-Xin and Kwong, Peter D. and Haynes, Barton F.},
abstractNote = {Here, we report that antibodies with ontogenies from VH1-2 or VH1-46-germline genes dominate the broadly neutralizing response against the CD4-binding site (CD4bs) on HIV-1. We define with longitudinal sampling from time-of-infection the development of a VH1-46-derived antibody lineage that matured to neutralize 90% of HIV-1 isolates. Structures of lineage antibodies CH235 (week 41 from time-of-infection, 18% breadth), CH235.9 (week 152, 77%), and CH235.12 (week 323, 90%) demonstrated the maturing epitope to focus on the conformationally invariant portion of the CD4bs. Similarities between CH235 lineage and five unrelated CD4bs lineages in epitope focusing, length-of-time to develop breadth, and extraordinary level of somatic hypermutation suggested commonalities in maturation among all CD4bs antibodies. Fortunately, the required CH235-lineage hypermutation appeared substantially guided by the intrinsic mutability of the VH1-46 gene, which closely resembled VH1-2. Lastly, we integrated our CH235-lineage findings with a second broadly neutralizing lineage and HIV-1 co-evolution to suggest a vaccination strategy for inducing both lineages.},
doi = {10.1016/j.cell.2016.02.022},
journal = {Cell},
number = 2,
volume = 165,
place = {United States},
year = {2016},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1016/j.cell.2016.02.022

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Works referencing / citing this record:

Progress toward active or passive HIV-1 vaccination
journal, December 2016

  • Escolano, Amelia; Dosenovic, Pia; Nussenzweig, Michel C.
  • The Journal of Experimental Medicine, Vol. 214, Issue 1
  • DOI: 10.1084/jem.20161765

Human adaptive immune receptor repertoire analysis-Past, present, and future
journal, June 2018

  • Nielsen, Sandra C. A.; Boyd, Scott D.
  • Immunological Reviews, Vol. 284, Issue 1
  • DOI: 10.1111/imr.12667

Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation
journal, May 2017


Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design
journal, August 2018


Progress toward active or passive HIV-1 vaccination
journal, December 2016

  • Escolano, Amelia; Dosenovic, Pia; Nussenzweig, Michel C.
  • The Journal of Experimental Medicine, Vol. 214, Issue 1
  • DOI: 10.1084/jem.20161765

Human adaptive immune receptor repertoire analysis-Past, present, and future
journal, June 2018

  • Nielsen, Sandra C. A.; Boyd, Scott D.
  • Immunological Reviews, Vol. 284, Issue 1
  • DOI: 10.1111/imr.12667

Gene-Specific Substitution Profiles Describe the Types and Frequencies of Amino Acid Changes during Antibody Somatic Hypermutation
journal, May 2017


Beyond Hot Spots: Biases in Antibody Somatic Hypermutation and Implications for Vaccine Design
journal, August 2018


Mechanisms of Adaptive Immunity to Porcine Reproductive and Respiratory Syndrome Virus
journal, June 2017

  • Rahe, Michael; Murtaugh, Michael
  • Viruses, Vol. 9, Issue 6
  • DOI: 10.3390/v9060148

Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site
journal, August 2016

  • Wibmer, Constantinos Kurt; Gorman, Jason; Anthony, Colin S.
  • Journal of Virology, Vol. 90, Issue 22
  • DOI: 10.1128/jvi.01357-16

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers
journal, September 2018