title: CCL19 and CCL28 augment mucosal and systemic immune responses to HIV-1 gp140 by mobilizing responsive immunocytes into secondary lymph nodes and mucosal tissue.
abstract: Induction of broad and potent neutralizing Abs at the mucosal portals of entry remains a primary goal for most vaccines against mucosally acquired viral infections. Selection of appropriate adjuvants capable of promoting both systemic and mucosal responses will be crucial for the development of effective immunization strategies. In this study, we investigated whether plasmid codelivery of cytokines APRIL, CCL19, or CCL28 can enhance Ag-induced immune responses to HIV-1 gp140. Our results demonstrated that pCCL19 and pCCL28, but not pAPRIL, significantly enhanced Ag-specific systemic and mucosal Ab responses. gp140-specific Abs in serum enhanced by pCCL19 or pCCL28 were broadly distributed across all four IgG subclasses, of which IgG1 was predominant. The enhanced systemic and mucosal Abs showed increased neutralizing activity against both homologous and heterologous HIV-1, and potency correlated with gp140-specific serum IgG and vaginal IgA levels. Measurement of gp140-specific cytokines produced by splenocytes demonstrated that pCCL19 and pCCL28 augmented balanced Th1/Th2 responses. pCCL19 and pCCL28 also increased IgA(+) cells in colorectal mucosal tissue. pCCL19 codelivery resulted in an increase of CCR7(+) CD11c(+) cells in mesenteric lymph nodes and both CCR7(+) CD11c(+) cells and CCR7(+) CD3e(+) cells in spleen, whereas pCCL28 codelivery resulted in an augment of CCR10(+) CD19(+) cells in both spleen and mesenteric lymph nodes. Together, our data indicate that pCCL19 and pCCL28 can enhance HIV-1 envelope-specific systemic and mucosal Ab responses, as well as T cell responses. Such enhancements appear to be associated with mobilization of responsive immunocytes into secondary lymphoid organs and mucosal tissues through interactions with corresponding receptors.
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Hu
authors.forename: Sukun
authors.initials: S
authors.lastname: Luo
authors.forename: Lina
authors.initials: L
authors.lastname: Tong
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Wenjie
authors.initials: W
authors.lastname: Huang
authors.forename: Tao
authors.initials: T
authors.lastname: Du
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.forename: Siyi
authors.initials: S
authors.lastname: He
authors.forename: George E
authors.initials: GE
authors.lastname: Griffin
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Shattock
authors.forename: Qinxue
authors.initials: Q
authors.lastname: Hu
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D054415:Chemokine CCL19 / Q000235:genetics / Q000502:physiology*; D019742:Chemokines, CC / Q000235:genetics / Q000502:physiology*; D002633:Chemotaxis; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000096:biosynthesis* / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000276:immunology; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000502:physiology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology; D014621:Vagina / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; C515461:Ccl19 protein, mouse; C511142:Ccl28 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D015483:HIV Antibodies; D007132:Immunoglobulin Isotypes; D011993:Recombinant Fusion Proteins; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1