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Title: Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site

Abstract

Antibodies that neutralize autologous transmitted/founder (TF) HIV occur in most HIV-infected individuals and can evolve to neutralization breadth. Autologous neutralizing antibodies (nAbs) against neutralization-resistant (Tier-2) viruses are rarely induced by vaccination. Whereas broadly neutralizing antibody (bnAb)-HIV-Envelope structures have been defined, the structures of autologous nAbs have not. Here, we show that immunization with TF mutant Envs gp140 oligomers induced high-titer, V5-dependent plasma neutralization for a Tier-2 autologous TF evolved mutant virus. Structural analysis of autologous nAb DH427 revealed binding to V5, demonstrating the source of narrow nAb specificity and explaining the failure to acquire breadth. Thus, oligomeric TF Envs can elicit autologous nAbs to Tier-2 HIVs, but induction of bnAbs will require targeting of precursors of B cell lineages that can mature to heterologous neutralization.

Authors:
 [1];  [2];  [3];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [4];  [5];  [1];  [6] more »;  [1];  [1];  [1];  [1];  [7];  [2];  [8];  [1] « less
+ Show Author Affiliations
  1. Duke Univ. School of Medicine, Durham, NC (United States)
  2. Harvard Medical School, Boston, MA (United States)
  3. National Inst. for Communicable Diseases, Johannesburg (South Africa); Univ. of the Witwatersrand, Johannesburg (South Africa)
  4. Univ. of KwaZulu-Natal, Durban (South Africa); Columbia Univ., New York, NY (United States)
  5. Novartis Vaccines and Diagnostics, Inc., Cambridge, MA (United States)
  6. Boston Univ., MA (United States)
  7. National Inst. for Communicable Diseases, Johannesburg (South Africa); Univ. of KwaZulu-Natal, Durban (South Africa); Univ. of the Witwatersrand, Johannesburg (South Africa)
  8. Harvard Medical School, Boston, MA (United States); Howard Hughes Medical Inst., Boston, MA (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
NIH/NIAID/DAIDS
OSTI Identifier:
1234757
Grant/Contract Number:  
1F32AI116355-01
Resource Type:
Accepted Manuscript
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 14; Journal Issue: 1; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Bradley, Todd, Fera, Daniela, Bhiman, Jinal, Eslamizar, Leila, Lu, Xiaozhi, Anasti, Kara, Zhang, Ruijung, Sutherland, Laura L., Scearce, Richard M., Bowman, Cindy M., Stolarchuk, Christina, Lloyd, Krissey E., Parks, Robert, Eaton, Amanda, Foulger, Andrew, Nie, Xiaoyan, Karim, Salim S. Abdool, Barnett, Susan, Kelsoe, Garnett, Kepler, Thomas B., Alam, S. Munir, Montefiori, David C., Moody, M. Anthony, Liao, Hua-Xin, Morris, Lynn, Santra, Sampa, Harrison, Stephen C., and Haynes, Barton F. Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site. United States: N. p., 2015. Web. doi:10.1016/j.celrep.2015.12.017.
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Bradley, Todd, Fera, Daniela, Bhiman, Jinal, Eslamizar, Leila, Lu, Xiaozhi, Anasti, Kara, Zhang, Ruijung, Sutherland, Laura L., Scearce, Richard M., Bowman, Cindy M., Stolarchuk, Christina, Lloyd, Krissey E., Parks, Robert, Eaton, Amanda, Foulger, Andrew, Nie, Xiaoyan, Karim, Salim S. Abdool, Barnett, Susan, Kelsoe, Garnett, Kepler, Thomas B., Alam, S. Munir, Montefiori, David C., Moody, M. Anthony, Liao, Hua-Xin, Morris, Lynn, Santra, Sampa, Harrison, Stephen C., & Haynes, Barton F. Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site. United States. https://doi.org/10.1016/j.celrep.2015.12.017
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Bradley, Todd, Fera, Daniela, Bhiman, Jinal, Eslamizar, Leila, Lu, Xiaozhi, Anasti, Kara, Zhang, Ruijung, Sutherland, Laura L., Scearce, Richard M., Bowman, Cindy M., Stolarchuk, Christina, Lloyd, Krissey E., Parks, Robert, Eaton, Amanda, Foulger, Andrew, Nie, Xiaoyan, Karim, Salim S. Abdool, Barnett, Susan, Kelsoe, Garnett, Kepler, Thomas B., Alam, S. Munir, Montefiori, David C., Moody, M. Anthony, Liao, Hua-Xin, Morris, Lynn, Santra, Sampa, Harrison, Stephen C., and Haynes, Barton F. Thu . "Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site". United States. https://doi.org/10.1016/j.celrep.2015.12.017. https://www.osti.gov/servlets/purl/1234757.
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@article{osti_1234757,
title = {Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site},
author = {Bradley, Todd and Fera, Daniela and Bhiman, Jinal and Eslamizar, Leila and Lu, Xiaozhi and Anasti, Kara and Zhang, Ruijung and Sutherland, Laura L. and Scearce, Richard M. and Bowman, Cindy M. and Stolarchuk, Christina and Lloyd, Krissey E. and Parks, Robert and Eaton, Amanda and Foulger, Andrew and Nie, Xiaoyan and Karim, Salim S. Abdool and Barnett, Susan and Kelsoe, Garnett and Kepler, Thomas B. and Alam, S. Munir and Montefiori, David C. and Moody, M. Anthony and Liao, Hua-Xin and Morris, Lynn and Santra, Sampa and Harrison, Stephen C. and Haynes, Barton F.},
abstractNote = {Antibodies that neutralize autologous transmitted/founder (TF) HIV occur in most HIV-infected individuals and can evolve to neutralization breadth. Autologous neutralizing antibodies (nAbs) against neutralization-resistant (Tier-2) viruses are rarely induced by vaccination. Whereas broadly neutralizing antibody (bnAb)-HIV-Envelope structures have been defined, the structures of autologous nAbs have not. Here, we show that immunization with TF mutant Envs gp140 oligomers induced high-titer, V5-dependent plasma neutralization for a Tier-2 autologous TF evolved mutant virus. Structural analysis of autologous nAb DH427 revealed binding to V5, demonstrating the source of narrow nAb specificity and explaining the failure to acquire breadth. Thus, oligomeric TF Envs can elicit autologous nAbs to Tier-2 HIVs, but induction of bnAbs will require targeting of precursors of B cell lineages that can mature to heterologous neutralization.},
doi = {10.1016/j.celrep.2015.12.017},
journal = {Cell Reports},
number = 1,
volume = 14,
place = {United States},
year = {Thu Dec 24 00:00:00 EST 2015},
month = {Thu Dec 24 00:00:00 EST 2015}
}
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    Works referencing / citing this record:

    Immunologic characteristics of HIV-infected individuals who make broadly neutralizing antibodies
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    • Gao, Yong; McKay, Paul; Mann, Jamie
    • Viruses, Vol. 10, Issue 4
    • DOI: 10.3390/v10040167
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