title: Novel CD8+ T cell-based vaccine stimulates Gp120-specific CTL responses leading to therapeutic and long-term immunity in transgenic HLA-A2 mice.
abstract: The limitations of highly active anti-retroviral therapy have necessitated the development of alternative therapeutics for human immunodeficiency virus type-1 (HIV-1)-infected patients with dysfunctional dendritic cells (DCs) and CD4(+) T cell deficiency. We previously demonstrated that HIV-1 Gp120-specific T cell-based Gp120-Texo vaccine by using ConA-stimulated C57BL/6 (B6) mouse CD8(+) T (ConA-T) cells with uptake of pcDNA(Gp120)-transfected B6 mouse DC line DC2.4 (DC2.4(Gp120))-released exosomes (EXO(Gp120)) was capable of stimulating DC and CD4(+) T cell-independent CD8(+) cytotoxic T lymphocyte (CTL) responses detected in wild-type B6 mice using non-specific PE-anti-CD44 and anti-IFN-γ antibody staining by flow cytometry. To assess effectiveness of Gp120-Texo vaccine in transgenic (Tg) HLA-A2 mice mimicking the human situation, we constructed adenoviral vector AdV(Gp120) expressing HIV-1 GP120 by recombinant DNA technology, and generated Gp120-Texo vaccine by using Tg HLA-A2 mouse CD8(+) ConA-T cells with uptake of AdV(Gp120)-transfected HLA-A2 mouse bone marrow DC (DC(Gp120))-released EXO(Gp120). We then performed animal studies to assess Gp120-Texo-induced stimulation of Gp120-specific CTL responses and antitumor immunity in Tg HLA-A2 mice. We demonstrate that Gp120-Texo vaccine stimulates Gp120-specific CTL responses detected in Tg HLA-A2 mice using Gp120-specific PE-HLA-A2/Gp120 peptide (KLTPLCVTL) tetramer staining by flow cytometry. These Gp120-specific CTLs are capable of further differentiating into functional effectors with killing activity to Gp120 peptide-pulsed splenocytes in vivo. In addition, Gp120-Texo vaccine also induces Gp120-specific preventive, therapeutic (for 6 day tumor lung metastasis) and CD4(+) T cell-independent long-term immunity against B16 melanoma BL6-10(Gp120/A2Kb) expressing both Gp120 and A2Kb (α1 and α2 domains of HLA-A2 and α3 domain of H-2K(b)) in Tg HLA-A2 mice. Taken together, the novel CD8(+) Gp120-Texo vaccine capable of stimulating efficient CD4(+) T cell-independent Gp120-specific CD8(+) CTL responses leading to therapeutic and long-term immunity in Tg HLA-A2 mice may represent a new immunotherapeutic vaccine for treatment of HIV-1 patients with CD4(+) T cell deficiency.
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Roopa Hebbandi
authors.initials: RH
authors.lastname: Nanjundappa
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.forename: Channakeshava Sokke
authors.initials: CS
authors.lastname: Umeshappa
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D005822:Genetic Vectors; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000628:therapy*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015699:HIV Envelope Protein gp120; D015789:HLA-A2 Antigen; C514793:gp120 protein, Human immunodeficiency virus 1