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

Authors: Josephine J Trichka; Andrew T. McGuire; Andrew T. McGuire; K. Rachael Parks; K. Rachael Parks; Connor Weidle; David C. Montefiori; +17 Authors

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.

Keywords

Male, B-Lymphocytes, QH301-705.5, env Gene Products, Human Immunodeficiency Virus, Antibodies, Monoclonal, Receptors, Antigen, B-Cell, HIV Infections, HIV Antibodies, Antibodies, Neutralizing, Article, Mice, Polysaccharides, CD4 Antigens, HIV-1, Animals, Female, Immunization, Biology (General), Immunoglobulin Heavy Chains, Broadly Neutralizing Antibodies

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
39
Top 10%
Top 10%
Top 10%
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