title: Beta7-integrin-independent enhancement of mucosal and systemic anti-HIV antibody responses following combined mucosal and systemic gene delivery.
abstract: Vaccination strategies that can block or limit heterosexual human immunodeficiency virus (HIV) transmissions to local and systemic tissues are the goal of much research effort. Herein, in a mouse model, we aimed to determine whether the enhancement of antibody responses through mucosal and systemic immunizations, previously observed with protein-based vaccines, applies to immunizations with DNA- or RNA-based vectors. Intranasal (i.n.) followed by intramuscular (i.m.) immunizations (i.n./i.m.) with polylactide-coglycolide (PLG)-DNA microparticles encoding HIV-gag (PLG-DNA-gag) significantly enhanced serum antibody responses, compared with i.m., i.n. or i.m. followed by i.n. (i.m./i.n.) immunizations. Moreover, while i.n./i.m., i.n. or i.m./i.n. immunizations with PLG-DNA-gag resulted in genital tract antibody responses, i.m. immunizations alone failed to do so. Importantly, beta7-deficient mice developed local and systemic antibody responses following i.n./i.m. immunization, or immunization via any other route, similar to those of wild-type mice. To compare the DNA with an RNA delivery system, immunizations were performed with VEE/SIN-gag replicon particles, composed of Venezuelan equine encephalitis virus (VEE) replicon RNA and Sindbis surface structure (SIN). i.n./i.m., compared with any other immunizations, i.n./i.m. immunization with VEE/SIN-gag resulted in enhanced genital tract but not serum antibody responses. These data show for the first time that mucosal followed by systemic immunizations with gene delivery systems enhance B-cell responses independent of the mucosal homing receptors alpha4beta7 and alphaEbeta7.
authors.affiliation: Novartis Vaccines and Diagnostics, Inc., Emeryville, CA 94608, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Goodsell
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhou
authors.forename: Soumi
authors.initials: S
authors.lastname: Gupta
authors.forename: Manmohan
authors.initials: M
authors.lastname: Singh
authors.forename: Padma
authors.initials: P
authors.lastname: Malyala
authors.forename: Jina
authors.initials: J
authors.lastname: Kazzaz
authors.forename: Catherine
authors.initials: C
authors.lastname: Greer
authors.forename: Harold
authors.initials: H
authors.lastname: Legg
authors.forename: Tony
authors.initials: T
authors.lastname: Tang
authors.forename: January
authors.initials: J
authors.lastname: Zur Megede
authors.forename: Ranjana
authors.initials: R
authors.lastname: Srivastava
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.forename: John J
authors.initials: JJ
authors.lastname: Donnelly
authors.forename: Paul A
authors.initials: PA
authors.lastname: Luciw
authors.forename: John
authors.initials: J
authors.lastname: Polo
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.forename: Michael
authors.initials: M
authors.lastname: Vajdy
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D004666:Encephalitis Virus, Venezuelan Equine / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D018014:Gene Transfer Techniques; D015483:HIV Antibodies / Q000096:biosynthesis*; D015497:HIV-1 / Q000276:immunology*; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods; D007273:Injections, Intramuscular; D039641:Integrin beta Chains / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011091:Polyesters; D012367:RNA, Viral / Q000276:immunology; D012093:Replicon / Q000276:immunology; D019444:Vaccines, DNA / Q000276:immunology; D014621:Vagina / Q000276:immunology
chemical_list: D015483:HIV Antibodies; D039641:Integrin beta Chains; D011091:Polyesters; D012367:RNA, Viral; D019444:Vaccines, DNA; C091368:integrin beta7; C033616:poly(lactide)