G-111 Identification of human long-lived plasma cells: Implications for HIV vaccines

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Abstract

Antibody responses to viral infections can be sustained for hundreds of years by long-lived plasma cells (LLPCs). The goal of any immunization is to maintain durability of serum antibody responses by the generation of LLPCs. However, LLPCs had yet to be characterized in humans. Here we used CD19, CD38 and CD138 to identify 4 distinct PC populations in the human bone marrow (BM). We show that the CD19−CD38hiCD138+ fraction is morphologically distinct and represents the exclusive repository of PCs specific for viral antigens to which the subjects had not been exposed for more than 40 years. We also show that protein sequences of viral-specific circulating antibodies are encoded exclusively by the BM CD19−CD38hiCD138+ PCs. Reconstitution of the monoclonal antibody from the BM PC RNA sequence demonstrates virus specificity. Additionally, Next Generation Sequencing (NGS) identifies a distinct VH repertoire of the CD19−CD38hiCD138+ subset that is relatively uncoupled from other BM PC subsets, suggesting that this compartment represents the B cell response’s “historical record” of antigenic exposure. Combined, our studies provide original evidence for a bone fide, discrete long-lived plasma cell compartment within the human BM and identify the ideal human PC compartment to generate vaccine-specificities including the HIV broadly neutralizing antibodies (HIV BNA).

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