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Title: Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization

Abstract

Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They are derived from VH1-2*02 antibody heavy chains paired with rare light chains expressing 5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in knockin mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that leads to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies.

Authors:
 [1];  [2];  [2];  [2];  [2];  [3];  [2];  [2];  [2];  [4];  [4];  [5];  [6];  [7];  [7];  [3];  [8];  [1];  [1]
  1. Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Global Health, University of Washington, Seattle, WA, USA
  2. Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  3. Department of Biochemistry, University of Washington, Seattle, WA, USA
  4. IAVI Neutralizing Antibody Center, Department of Immunology and Microbiology, The Scripps Research Institute, San Diego, CA, USA
  5. Department of Global Health, University of Washington, Seattle, WA, USA; Infectious Disease Research Institute, Seattle, WA, USA
  6. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
  7. Laboratory for AIDS Vaccine Research and Development, Duke University, Durham, NC, USA
  8. Vaccines and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Vaccine Research Center, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); Pew Charitable Trust; Burroughs Wellcome Fund; Arnold and Mabel Beckman Cryo-EM Center; J.B. Pendleton Charitable Trust
OSTI Identifier:
1623651
Grant/Contract Number:  
AC02-05CH11231; R01 AI104384; P01 AI138212; U19 AI109632; HHSN272201800004C; R01GM120553
Resource Type:
Accepted Manuscript
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 29; Journal Issue: 10; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cell Biology

Citation Formats

Parks, K. Rachael, MacCamy, Anna J., Trichka, Josephine, Gray, Matthew, Weidle, Connor, Borst, Andrew J., Khechaduri, Arineh, Takushi, Brittany, Agrawal, Parul, Guenaga, Javier, Wyatt, Richard T., Coler, Rhea, Seaman, Michael, LaBranche, Celia, Montefiori, David C., Veesler, David, Pancera, Marie, McGuire, Andrew, and Stamatatos, Leonidas. Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization. United States: N. p., 2019. Web. https://doi.org/10.1016/j.celrep.2019.10.071.
Parks, K. Rachael, MacCamy, Anna J., Trichka, Josephine, Gray, Matthew, Weidle, Connor, Borst, Andrew J., Khechaduri, Arineh, Takushi, Brittany, Agrawal, Parul, Guenaga, Javier, Wyatt, Richard T., Coler, Rhea, Seaman, Michael, LaBranche, Celia, Montefiori, David C., Veesler, David, Pancera, Marie, McGuire, Andrew, & Stamatatos, Leonidas. Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization. United States. https://doi.org/10.1016/j.celrep.2019.10.071
Parks, K. Rachael, MacCamy, Anna J., Trichka, Josephine, Gray, Matthew, Weidle, Connor, Borst, Andrew J., Khechaduri, Arineh, Takushi, Brittany, Agrawal, Parul, Guenaga, Javier, Wyatt, Richard T., Coler, Rhea, Seaman, Michael, LaBranche, Celia, Montefiori, David C., Veesler, David, Pancera, Marie, McGuire, Andrew, and Stamatatos, Leonidas. Sun . "Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization". United States. https://doi.org/10.1016/j.celrep.2019.10.071. https://www.osti.gov/servlets/purl/1623651.
@article{osti_1623651,
title = {Overcoming Steric Restrictions of VRC01 HIV-1 Neutralizing Antibodies through Immunization},
author = {Parks, K. Rachael and MacCamy, Anna J. and Trichka, Josephine and Gray, Matthew and Weidle, Connor and Borst, Andrew J. and Khechaduri, Arineh and Takushi, Brittany and Agrawal, Parul and Guenaga, Javier and Wyatt, Richard T. and Coler, Rhea and Seaman, Michael and LaBranche, Celia and Montefiori, David C. and Veesler, David and Pancera, Marie and McGuire, Andrew and Stamatatos, Leonidas},
abstractNote = {Broadly HIV-1 neutralizing VRC01 class antibodies target the CD4-binding site of Env. They are derived from VH1-2*02 antibody heavy chains paired with rare light chains expressing 5-amino acid-long CDRL3s. They have been isolated from infected subjects but have not yet been elicited by immunization. Env-derived immunogens capable of binding the germline forms of VRC01 B cell receptors on naive B cells have been designed and evaluated in knockin mice. However, the elicited antibodies cannot bypass glycans present on the conserved position N276 of Env, which restricts access to the CD4-binding site. Efforts to guide the appropriate maturation of these antibodies by sequential immunization have not yet been successful. Here, we report on a two-step immunization scheme that leads to the maturation of VRC01-like antibodies capable of accommodating the N276 glycan and displaying autologous tier 2 neutralizing activities. Our results are relevant to clinical trials aiming to elicit VRC01 antibodies.},
doi = {10.1016/j.celrep.2019.10.071},
journal = {Cell Reports},
number = 10,
volume = 29,
place = {United States},
year = {2019},
month = {12}
}

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