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and R.P. FO phenotype, respectively. Murine FO B cells express a diverse antibody repertoire to recognize gp120. In contrast, mouse MZ B cells recognize gp120 less frequently but preferentially use to encode gp120-specific antibodies. Notably, shows high identity to human expression is enriched in mouse MZ B cells. These data suggest that efforts toward developing an HIV vaccine might consider eliciting protective HIV antibody responses selectively from alternative B-cell populations harboring gene segments capable of producing protective antibodies. gene segment to encode the Ig heavy chain. Structural studies have shown that the complementary determining region 2 (CDRH2) of that encodes VRC01 confers broad neutralization by binding the most vulnerable and conserved portion of the CD4 binding site on gp120 (14). The CDRH2 of VRC01 and related antibodies is considerably mutated from the germ line. These findings suggest that promoting HIV neutralization by targeting B cells bearing this IGHV segment may provide a promising vaccine strategy. A successful HIV vaccine must be able to promote neutralizing antibody responses over the dominant nonprotective responses. Accomplishing this Maritoclax (Marinopyrrole A) may require the specific participation of different B-cell subsets. The antibody response to physiological pathogens is a cooperative effort between different B-cell subpopulations (15). The major B-cell populations, CD21+CD23+ follicular (FO) cells in mice and IgD+CD27C na?ve B cells in humans, require the help of cognate T cells to respond to protein antigens to produce class-switched, affinity-matured antibodies and memory B cells, a process that takes time to develop. In addition, early after infection, marginal zone (MZ) B cells mount rapid antibody responses to repetitive epitopes displayed by pathogens and are not necessarily dependent on T-cell help. It is widely believed that MZ B cells do not participate in germinal center reactions and thus do not somatically mutate Ig genes, although independent studies have shown the direct ability of mouse MZ B cells to induce germinal centers and undergo somatic hypermutation (16, 17). Furthermore, the human antibody response to the capsular polysaccharide of both and are dominated by IgM+IgD+CD27+ MZ-like human B cells (18C20) and are often mutated (21C24), indicating that MZ B cells are able to undergo somatic hypermutation when responding to bona fide pathogens. Qualitatively, antibodies from MZ Maritoclax (Marinopyrrole A) B cells are more often polyreactive than antibodies from FO B cells (25). This polyreactivity may be particularly beneficial in protecting against Maritoclax (Marinopyrrole A) HIV, which has an extremely low surface envelope spike density, making heteroligation to a viral spike and another antigen potentially important for virus neutralization (7, 26). This second antigen may be a self-antigen on the surface Maritoclax (Marinopyrrole A) of an infected cell or an HIV virion. Thus, the rarity of B cells that produce Rabbit polyclonal to HPCAL4 broadly neutralizing antibodies may be in part due to peripheral tolerance mechanisms that would impede the activation and differentiation of polyreactive B cells during the immune response to HIV (27). In this study, we examined B cells in na?ve mice to assess the preimmune repertoire available for a primary antibody response to the HIV envelope protein gp120. We found that the majority of B cells capable of responding to gp120 are FO cells in WT mice and na?ve B cells in uninfected human adults, suggesting that these B cells likely dominate the primary response to gp120. We also found that murine MZ B cells are able to recognize gp120, but do so using a restricted antibody repertoire dominated by antibodies harboring a specific Maritoclax (Marinopyrrole A) gene segment. Of note, this murine gene is most closely related to the gene used by the broadly neutralizing human VRC01 and related antibodies. Our findings suggest that a protective HIV vaccine might involve eliciting broadly neutralizing antibodies from B-cell populations that use gene segments known to generate protective antibodies. Results Most gp120-Reactive Na?ve B Cells Are of Follicular Origin. The antibody.