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

• DOI: 10.1371/journal.ppat.1009025
• Publication Date: 2020-11-30T19:05:50Z
• Authors: Véronique Godot; Colas Tcherakian; Laurine Gil; Iñaki Cervera-Marzal; Guangming Li; Liang Cheng; Nicolas Ortonne; Jean-Daniel Lelièvre; Giuseppe Pantaleo; Craig Fenwick; Mireille Centlivre; Hugo Mouquet; Sylvain Cardinaud; Sandra M. Zurawski; Gerard Zurawski; Pierre Milpied; Lishan Su; Yves Lévy
• Keywords: Naive B cell; TLR3

The development of HIV-1 vaccines is challenged by the lack relevant models to accurately induce human B- and T-cell responses in lymphoid organs. In humanized mice reconstituted with hematopoietic stem cells (hu-mice), B cell-development function are impaired fail efficiently transition from IgM IgG cells. Here, we found that CD40-targeted vaccination combined CpG-B adjuvant overcomes usual defect B-cell switch maturation hu-mice. We further dissected hu-B cell directed against Env protein elicited targeting gp140 clade C CD40 receptor antigen-presenting anti-CD40.Env vaccine was injected a homologous prime/boost regimen or as boost NYVAC-KC pox vector encoding C. Both regimens Env-specific IgG-switched memory at greater magnitude hu-mice primed NYVAC-KC. Single-cell RNA-seq analysis showed gp140-specific express polyclonal IgG1 IgG3 isotypes broad Ig VH/VL repertoire, predominant VH3 family gene usage. These exhibited higher rate somatic hypermutation than non-specific + hu-B-cell counterpart. induced splenic GC-like structures containing hu-Tfh-like expressing PD-1 BCL-6. confirmed this model circulating ICOS hu-Tfh correlated responses. Finally, heterologous prime led more diverse clonal expansion specific Thus, study shows induces production provides insights for CD40-targeting prevent infection humans.