TLR-9 agonist and CD40-targeting vaccination induces HIV-1 envelope-specific B cells with a diversified immunoglobulin repertoire in humanized mice

The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to ef...

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Published inPLoS pathogens Vol. 16; no. 11; p. e1009025
Main Authors Godot, Véronique, Tcherakian, Colas, Gil, Laurine, Cervera-Marzal, Iñaki, Li, Guangming, Cheng, Liang, Ortonne, Nicolas, Lelièvre, Jean-Daniel, Pantaleo, Giuseppe, Fenwick, Craig, Centlivre, Mireille, Mouquet, Hugo, Cardinaud, Sylvain, Zurawski, Sandra M., Zurawski, Gerard, Milpied, Pierre, Su, Lishan, Lévy, Yves
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 30.11.2020
Public Library of Science (PLoS)
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ISSN1553-7374
1553-7366
1553-7374
DOI10.1371/journal.ppat.1009025

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Summary:The development of HIV-1 vaccines is challenged by the lack of relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with human hematopoietic stem cells (hu-mice), human B cell-development and function are impaired and cells fail to efficiently transition from IgM B cells to IgG B cells. Here, we found that CD40-targeted vaccination combined with CpG-B adjuvant overcomes the usual defect of human B-cell switch and maturation in hu-mice. We further dissected hu-B cell responses directed against the HIV-1 Env protein elicited by targeting Env gp140 clade C to the CD40 receptor of antigen-presenting cells. The anti-CD40.Env gp140 vaccine was injected with CpG-B in a homologous prime/boost regimen or as a boost of a NYVAC-KC pox vector encoding Env gp140 clade C. Both regimens elicited Env-specific IgG-switched memory hu-B cells at a greater magnitude in hu-mice primed with NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific hu-B cells to express polyclonal IgG1 and IgG3 isotypes and a broad Ig VH/VL repertoire, with predominant VH3 family gene usage. These cells exhibited a higher rate of somatic hypermutation than the non-specific IgG + hu-B-cell counterpart. Both vaccine regimens induced splenic GC-like structures containing hu-B and hu-Tfh-like cells expressing PD-1 and BCL-6. We confirmed in this model that circulating ICOS + memory hu-Tfh cells correlated with the magnitude of gp140-specific B-cell responses. Finally, the NYVAC-KC heterologous prime led to a more diverse clonal expansion of specific hu-B cells. Thus, this study shows that CD40-targeted vaccination induces human IgG production in hu-mice and provides insights for the development of a CD40-targeting vaccine to prevent HIV-1 infection in humans.
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PMCID: PMC7728200
I have read the journal's policy and the authors of this manuscript have the following competing interests: GZ, SZ, and YL are named inventors on CD40-targeting vaccine patents and patent filings held jointly by INSERM and the Baylor Research Institute.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1009025