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Tytuł:
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Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization.
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Autorzy:
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Aljedani SS; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
Liban TJ; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
Tran K; The Scripps Research Institute, IAVI Neutralizing Antibody Center, La Jolla, California, United States of America.
Phad G; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Singh S; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
Dubrovskaya V; The Scripps Research Institute, IAVI Neutralizing Antibody Center, La Jolla, California, United States of America.
Pushparaj P; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Martinez-Murillo P; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Rodarte J; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
Mileant A; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
Mangala Prasad V; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
Kinzelman R; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
O'Dell S; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Mascola JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Lee KK; Department of Medicinal Chemistry, University of Washington, Seattle, Washington, United States of America.
Karlsson Hedestam GB; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Wyatt RT; The Scripps Research Institute, IAVI Neutralizing Antibody Center, La Jolla, California, United States of America.; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, United States of America.
Pancera M; Fred Hutchinson Cancer Research Center, Vaccine and Infectious Disease Division, Seattle, Washington, United States of America.
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Źródło:
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PLoS pathogens [PLoS Pathog] 2021 Sep 24; Vol. 17 (9), pp. e1009543. Date of Electronic Publication: 2021 Sep 24 (Print Publication: 2021).
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: San Francisco, CA : Public Library of Science, c2005-
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MeSH Terms:
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AIDS Vaccines/*immunology
Antibodies, Neutralizing/*immunology
HIV Antibodies/*immunology
Immunodominant Epitopes/*immunology
env Gene Products, Human Immunodeficiency Virus/*immunology
Animals ; Antibodies, Monoclonal ; Epitopes, B-Lymphocyte/immunology ; Female ; HIV Infections/immunology ; HIV-1/immunology ; Macaca mulatta
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Grant Information:
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T32 AI007509 United States AI NIAID NIH HHS; UM1 AI144462 United States AI NIAID NIH HHS; R01 AI145055 United States AI NIAID NIH HHS; P01 AI157299 United States AI NIAID NIH HHS; S10 OD021832 United States OD NIH HHS; T32 GM007750 United States GM NIGMS NIH HHS; R01 AI140868 United States AI NIAID NIH HHS
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Substance Nomenclature:
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0 (AIDS Vaccines)
0 (Antibodies, Monoclonal)
0 (Antibodies, Neutralizing)
0 (Epitopes, B-Lymphocyte)
0 (HIV Antibodies)
0 (Immunodominant Epitopes)
0 (env Gene Products, Human Immunodeficiency Virus)
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Entry Date(s):
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Date Created: 20210924 Date Completed: 20211124 Latest Revision: 20221230
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Update Code:
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20240105
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PubMed Central ID:
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PMC8494329
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DOI:
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10.1371/journal.ppat.1009543
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PMID:
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34559844
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Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 μg/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide potential explanations for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.
Competing Interests: The authors have declared that no competing interests exist.
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