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.