title: Increased level and longevity of protective immune responses induced by DNA vaccine expressing the HIV-1 Env glycoprotein when combined with IL-21 and IL-15 gene delivery.
abstract: We investigated the ability of a plasmid-derived IL-21 delivered alone or in combination with the IL-15 gene to regulate immune responses to the HIV-1 envelope (Env) glycoprotein induced by DNA vaccination. Mice were injected with the gp140DeltaCFI(HXB2/89.6) vector expressing a modified Env glycoprotein with C-terminal mutations intended to mimic a fusion intermediate, in which the most divergent region encoding the variable V1, V2, and V3 domains of CXCR4-tropic HxB2 virus was replaced with the dual-tropic 89.6 viral strain. Using a recombinant vaccinia virus expressing 89.6 Env glycoprotein (vBD3) in a mouse challenge model, we observed that IL-21 plasmid produced sustained resistance to viral transmission when injected 5 days after DNA vaccination. Moreover, IL-21 in a synergistic manner with IL-15 expression vector augmented the vaccine-induced recall responses to the vBD3 challenge compared with those elicited by immunization in the presence of either cytokine alone. The synergistic combination of IL-21 and IL-15 plasmids promoted expansion of CD8+CD127+ memory T cell pools specific for a subdominant HLA-A2-restricted Env(121-129) epitope (KLTPLCVTL). Our results also show that coimmunization with IL-21 and IL-15 plasmid combination resulted in enhanced CD8+ T cell function that was partially independent of CD4+ T cell help in mediating protection against vBD3 challenge. Furthermore, the use of IL-21 and IL-15 genes was able to increase Ab-dependent cellular cytotoxicity and complement-dependent lysis of Env-expressing target cells through augmentation of Env-specific IgG Ab levels. These data indicate that the plasmid-delivered IL-21 and IL-15 can increase the magnitude of the response to DNA vaccines.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bolesta
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kowalczyk
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wierzbicki
authors.forename: Cheryl
authors.initials: C
authors.lastname: Eppolito
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takiguchi
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.forename: Protul A
authors.initials: PA
authors.lastname: Shrikant
authors.forename: Danuta
authors.initials: D
authors.lastname: Kozbor
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics*; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003131:Combined Modality Therapy; D005260:Female; D015686:Gene Products, env / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D018014:Gene Transfer Techniques; D015483:HIV Antibodies / Q000096:biosynthesis / Q000502:physiology; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D007117:Immunization, Secondary; D019409:Interleukin-15 / Q000008:administration & dosage / Q000235:genetics*; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009500:Neutralization Tests; D011817:Rabbits; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus; D000098546:Interleukin-21
chemical_list: D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D015686:Gene Products, env; D015483:HIV Antibodies; D019409:Interleukin-15; D007378:Interleukins; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1; D000098546:Interleukin-21