Abstract

Abstract The most potent and broad HIV envelope (Env)-specific antibodies (Abs) often when reverted to their inferred germline versions representing the naïve B cell receptor, usually fail to bind Env. This may suggest that the primary B cell population that responds to the initial Env exposure is not exclusively comprised of a naïve population, but also a pre-existing cross-reactive antigen-experienced B cell pool that expands following Env exposure. Previously we isolated 66 gp120 reactive mAbs from participants from HVTN105, a phase I trial testing AIDSVAX B/E (gp120 protein) combined with a DNA immunogen. In order to determine the origin of these mAb producing B cells, we used Miseq-based VH lineage tracking approach and identified several of these mAb lineages in peripheral blood prior to vaccination (pre-immune). Further, several of these pre-immune lineages also persist in the bone marrow ~8 months after the final vaccination, including within in the CD138+ long-lived plasma cell compartment. When tested by ELISA, pre-immune mAbs bound to HIV Env, with relatively lower ability than their post-vaccination forms, but showed higher reactivity than their germline form. The majority of the pre-immune lineage members were IgM, however IgG and IgA members were predominant prior to vaccination and the majority of the pre-immune lineage members exhibited somatic hypermutation. These results may indicate that the vaccine-induced Env-specific antibody lineages originated from a mixed ancestor population of naïve and cross-reactive memory cells.

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