Mouse marginal zone B cells harbor specificities similar to human broadly neutralizing HIV antibodies

Abstract

A series of potent, broadly neutralizing HIV antibodies have been isolated from B cells of HIV-infected individuals. VRC01 represents a subset of these antibodies that mediate neutralization with a restricted set of IGHV genes. The memory B cells expressing these antibodies were isolated years after infection; thus, the B-cell subpopulation from which they originated and the extent of participation in the initial HIV antibody response, if any, are unclear. Here we evaluated the frequency of anti-gp120 B cells in follicular (FO) and marginal zone (MZ) B-cell compartments of naïve WT mice and comparable human populations in uninfected individuals. We found that in non-HIV-exposed humans and mice, the majority of gp120-reactive B cells are of naïve and 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 IGHV1-53 to encode gp120-specific antibodies. Notably, IGHV1-53 shows high identity to human IGHV1-2*02, which has been repeatedly found to encode broadly neutralizing mutated HIV antibodies, such as VRC01. Finally, we show that human MZ-like B cells express IGHV1-2*02, and that IGHV1-53 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 IGHV gene segments capable of producing protective antibodies.B-cell subsets | virus | germ line | polyreactive

Breaching peripheral tolerance promotes the production of HIV-1–neutralizing antibodies

“…In humans, the anti-gp160 antibody response to HIV-1 has been shown to predominantly arise from poly-/autoreactive mature B cells ( Mouquet et al, 2011 ; Mouquet and Nussenzweig, 2012 ). In mice, transitional, anergic and marginal zone B cell subpopulations have all been characterized to express a poly-/autoreactive antibody repertoire ( Chen et al, 1997 ; Carey et al, 2008 ), and we previously reported that marginal zone B cells from naive wild-type B6 mice often express a gp120-reactive antibody receptor that also displays autoreactivity toward nuclear antigens ( Pujanauski et al, 2013 ). Which of these B cell populations, if any, is responsible for tier 2 HIV-neutralizing activity and whether Env-elicited HIV-1–neutralizing B cells can develop into memory B cells remains to be determined but can be addressed with mouse models.…”

DNA Vaccine Molecular Adjuvants SP-D-BAFF and SP-D-APRIL Enhance Anti-gp120 Immune Response and Increase HIV-1 Neutralizing Antibody Titers

“…Another likely possibility is that the neutralizing antibodies observed arise from broadly reactive marginal zone B cells through affinity maturation. Mouse marginal zone B cells have recently been shown to harbor specificities similar to those of human bNAbs (10).…”

“…Thus, the mature B cell repertoire likely contains weakly HIV-1 reactive B cell clones, as well as some strongly reactive B cell clones that escape tolerance checkpoints or assume an anergic state. Recent evidence suggests that the mature B cell repertoire in both mice and humans contains clones that bind HIV-1 Env and are often polyreactive (9,10). Thus, in principle, it should be possible to design vaccines targeting HIV envelope-specific B cells that can serve as precursors for anti-HIV-1 bNAbs (7,11).…”

Autoreactivity in HIV-1 broadly neutralizing antibodies

“…In addition, a large proportion of other B-cell subsets (i.e. MZ, B-1) (71,72), recently shown to harbor specificities resembling those of some BnAbs (73) also exhibit in vitro poly-/autoreactivity. “False negatives” can result from technical inter or intra-assay variation between laboratories.…”