title: BLyS-mediated modulation of naive B cell subsets impacts HIV Env-induced antibody responses.
abstract: Neutralizing Abs provide the protective effect of the majority of existing human vaccines. For a prophylactic vaccine against HIV-1, broadly neutralizing Abs targeting conserved epitopes of the viral envelope glycoproteins (Env) are likely required, because the pool of circulating HIV-1 variants is extremely diverse. The failure to efficiently induce broadly neutralizing Abs by vaccination may be due to the use of suboptimal immunogens or immunization regimens, or it may indicate that B cells specific for broadly neutralizing Env determinants are selected against during peripheral checkpoints, either before or after Ag encounter. To investigate whether perturbation of B cell subsets prior to immunization with recombinant Env protein affects the vaccine-induced Ab response in mice, we used B lymphocyte stimulator (BLyS), a cytokine that regulates survival and selection of peripheral B cells. We show that the transient BLyS treatment used in this study substantially affected naive B cell populations; in particular, it resulted in more B cells surviving counter-selection at the transitional stages. We also observed more mature naive B cells, especially marginal zone B cells, in BLyS-treated mice. Intriguingly, provision of excess BLyS prior to immunization led to a consistent improvement in the frequency and potency of HIV-1 Env vaccine-induced neutralizing Ab responses, without increasing the number of Env-specific Ab-secreting cells or the Ab-binding titers measured after boosting. The results presented in this article suggest that an increased understanding of BLyS-regulated processes may help the design of vaccine regimens aimed at eliciting improved neutralizing Ab responses against HIV-1.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: Pia
authors.initials: P
authors.lastname: Dosenovic
authors.forename: Martina
authors.initials: M
authors.lastname: Soldemo
authors.forename: Jean L
authors.initials: JL
authors.lastname: Scholz
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.forename: Emilie K
authors.initials: EK
authors.lastname: Grasset
authors.forename: Nadège
authors.initials: N
authors.lastname: Pelletier
authors.forename: Mikael C I
authors.initials: MC
authors.lastname: Karlsson
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Richard T
authors.initials: RT
authors.lastname: Wyatt
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
authors.forename: Gunilla B
authors.initials: GB
authors.lastname: Karlsson Hedestam
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D015483:HIV Antibodies / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D011994:Recombinant Proteins / Q000276:immunology; D014162:Transfection; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D053264:B-Cell Activating Factor; D018985:Epitopes, B-Lymphocyte; D015483:HIV Antibodies; D011994:Recombinant Proteins; D054299:env Gene Products, Human Immunodeficiency Virus