Novel CD8+ T cell-based vaccine stimulates Gp120-specific CTL responses leading to therapeutic and long-term immunity in transgenic HLA-A2 mice

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 pcDNAGp120-transfected B6 mouse DC line DC2.4 (DC2.4Gp120)-released exosomes (EXOGp120) 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 AdVGp120 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 AdVGp120-transfected HLA-A2 mouse bone marrow DC (DCGp120)-released EXOGp120. 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 BL6-10Gp120/A2Kb expressing both Gp120 and A2Kb (α1 and α2 domains of HLA-A2 and α3 domain of H-2Kb) 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.

► We generated Gp120-Texo vaccine using HLA-A2 CD8+ ConA-T cells up-taking EXOGp120.
► Gp120-Texo vaccine stimulates Gp120-specific CD4+ T cell-independent CTL response.
► Gp120-Texo induces Gp120-specific therapeutic and long-term immunity in HLA-A2 mice.