Abstract
Human immunodeficiency virus type-1 (HIV-1) chronic infection causes millions of deaths each year. We previously developed a novel HIV-1 Gag-spe cific exosome (EXO)-targeted T cell-based vaccine (Gag-Texo) using ConAstimulated polyclonal CD8+T (ConA-T) cells armed with Gag-specific dendritic cell (DC)-released EXOs, and showed that Gag-Texo stimulated more efficient cytotoxic T lymphocyte (CTL) responses than DCs. Tat HIV-1 early regulatory protein possesses immunomodulatory and adjuvant properties. To enhance Gag-Texo immunogenicity, we generated Tat-engineered OVA/Tat Texo and Gag/Tat-Texo vaccines using ConA-T cells armed with EXOs release by DCs infected with recombinant OVA/Tat- and Gag/Tat-expressing adenoviruses (AdVOVA/Tat and AdVGag/Tat). We then assessed vaccination-stimulated CTL responses in naive mice, and therapeutic immunity in transgenic HLA-A2 mice bearing Gag/HLA-A2-expressing BL6-10OVA/A2 melanoma lung metastases. We demonstrate that the OVA/Tat-Texo vaccine enhances functional OVA-specific CTL responses, compared to the OVA-Texo vaccine, and broadens CTL responses recognizing the cryptic OVA epitope in C57BL/6 mice. Furthermore, we determine that the Gag/Tat-Texo not only stimulates more efficient CTL responses than Gag-Texo, but also induces enhanced therapeutic immunity. We show that, 30% of Gag/Tat-Texo-immunized mice are free of tumor lung-metastases, compared to all Gag-Texo-immunized mice displaying lung-metastasis. In addition, the average number of tumor lung metastases colonies (32/lung) in the Gag/Tat-Texo-immunized mice was also significantly lower than that (78/lung) observed in Gag-Texo-immunized mice. Taken together, this indicates that HIV-1 Gag/Tat-Texo capable of stimulating enhanced Gag-specific CTL responses and therapeutic immunity may become a new immunotherapeutic vaccine candidate for controlling virus in HIV-1 patients.
Highlights
Human immunodeficiency virus type-1 (HIV-1) that causes millions of deaths each year primarily acts by infecting memory CD4+ CCR5+ T cells, and becomes resistant to antiviral drug therapy (ART)
We previously developed a novel HIV-1 Gag-spe cific exosome (EXO)-targeted T cell-based vaccine (Gag-Texo) using ConAstimulated polyclonal CD8+ T (ConA-T) cells armed with Gag-specific dendritic cell (DC)-released EXOs, and showed that Gag-Texo stimulated more efficient cytotoxic T lymphocyte (CTL) responses than DCs
We demonstrated that the Gp120-Texo vaccine was more immunogenic than the DCGp120 vaccine and was capable of stimulating CD4+ T cell-independent Gp120specific CTL responses, leading to protective and long-term immunity against Gp120/HLA-A2-expressing B16 melanoma (BL6-10Gp120/A2) in transgenic HLAA2 mice [13] [14]
Summary
HIV-1 that causes millions of deaths each year primarily acts by infecting memory CD4+ CCR5+ T cells, and becomes resistant to antiviral drug therapy (ART). This results in latent pro-viral reservoirs and a life-long infection [1]. “elite” control), potent CTLs can control it by killing virus-infected cells [2], leading to renewed interests in therapeutic vaccination for stimulating CTL responses decaying pro-viral reservoirs after pharmacologically purging the reservoirs [3]. Purging the reservoir itself is not sufficient to cause death of infected cells that remain in a resting state [4], whereas boosting CTL responses efficiently eliminates latent pro-viral reservoirs [4] [5], warranting a search for potent therapeutic vaccines. Functional CTL exhaustion becomes another chief issue, leading to ineffective HIV-1 control in patients [11] [12]
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