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Proc Natl Acad Sci U S A ; 117(37): 22920-22931, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32873644

RESUMO

Animal models of human antigen-specific B cell receptors (BCRs) generally depend on "inferred germline" sequences, and thus their relationship to authentic naive human B cell BCR sequences and affinities is unclear. Here, BCR sequences from authentic naive human VRC01-class B cells from healthy human donors were selected for the generation of three BCR knockin mice. The BCRs span the physiological range of affinities found in humans, and use three different light chains (VK3-20, VK1-5, and VK1-33) found among subclasses of naive human VRC01-class B cells and HIV broadly neutralizing antibodies (bnAbs). The germline-targeting HIV immunogen eOD-GT8 60mer is currently in clinical trial as a candidate bnAb vaccine priming immunogen. To attempt to model human immune responses to the eOD-GT8 60mer, we tested each authentic naive human VRC01-class BCR mouse model under rare human physiological B cell precursor frequency conditions. B cells with high (HuGL18HL) or medium (HuGL17HL) affinity BCRs were primed, recruited to germinal centers, and they affinity matured, and formed memory B cells. Precursor frequency and affinity interdependently influenced responses. Taken together, these experiments utilizing authentic naive human VRC01-class BCRs validate a central tenet of germline-targeting vaccine design and extend the overall concept of the reverse vaccinology approach to vaccine development.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Vacinas contra a AIDS/imunologia , Sequência de Aminoácidos/genética , Animais , Anticorpos Neutralizantes/imunologia , Linfócitos B/imunologia , Anticorpos Amplamente Neutralizantes/farmacologia , Antígenos CD4/imunologia , Técnicas de Introdução de Genes/métodos , Centro Germinativo/imunologia , Antígenos HIV , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Células Precursoras de Linfócitos B/imunologia , Vacinação/métodos
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