title: Divergence of primary cognate B- and T-cell proliferative responses to subcutaneous and intravenous immunization with virus-like particles.
abstract: A major advantage of virus-like particle (VLP) vaccines against HIV is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter the envelope protein in its natural conformation. For the induction of affinity-matured antibodies, the B-cells must also obtain help from T-cells that are restricted by linear epitopes. Using B- and T-cell transgenic mouse models, we compared the efficacy of modified HIV-VLPs delivered by subcutaneous and intravenous immunization to stimulate primary B- and T-cell proliferative responses in different lymphoid organs. VLPs containing an influenza virus hemagglutinin epitope within the HIV-Gag protein induced comparable primary cognate T-cell proliferative responses in the draining lymph node and the spleen, irrespective of the delivery route. In contrast, after subcutaneous immunization with HIV-Gag VLPs containing hen egg lysozyme (HEL) on their surface, the proliferative response of transgenic HEL-specific B-cells was restricted to the draining lymph nodes, while intravenous VLP immunization primarily induced a B-cell proliferative response in the spleen. In vitro co-culture experiments further revealed that the presentation of VLP-associated surface antigens by dendritic cells to cognate B-cells is inefficient. This is consistent with a direct triggering of the B-cell proliferative response by the VLPs and suggests that HIV VLPs may indeed be suitable to directly promote the expansion of B-cells specific for conformational epitopes that are unique to functionally-active Env spikes on the virion. Further investigations are warranted to explore potential differences in the quality and protective potency of HIV-specific antibody responses induced by the two routes.
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, D-44780, Germany. temchura@yandex.com.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Temchura
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, D-44780, Germany. svetlana.kalinin@ruhr-uni-bochum.de.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Kalinin
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, D-44780, Germany. ghulam.nabi@ruhr-uni-bochum.de.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Nabi
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, D-44780, Germany. bettina.g.tippler@rub.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Tippler
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, D-44780, Germany. thomas.niezold@gmx.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Niezold
authors.affiliation: Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, D-44780, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Uberla
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D061605:Administration, Intravenous; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology; D007279:Injections, Subcutaneous; D008198:Lymph Nodes / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009113:Muramidase / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination / Q000379:methods; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage* / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011993:Recombinant Fusion Proteins; D058425:Vaccines, Virus-Like Particle; D054301:gag Gene Products, Human Immunodeficiency Virus; D009113:Muramidase