The adjuvant effects of chemokines and cytokines on HIV DNA vaccine design.

摘要

The demonstration that DNA vaccines can elicit immune response to viral antigens has attracted great interest in applying this strategy on human immunodeficiency virus (HIV) vaccine development; however, the efficacy of DNA vaccines remains to be optimized to fully realize their potentials. Controlled release of Granulocyte-macrophage colony stimulating factor (GM-CSF) protein was established. In murine studies, T cell responses were enhanced by GM-CSF microparticles. Enhancement of antibody and T cell responses was observed after the first immunization in macaques with GM-CSF-microparticles and Gag plasmids. Gag protein in Freund's adjuvant enhanced antibody and T helper responses, but not Gag-specific Cytotoxic T lymphocytes (CTL). CTL was triggered by microspheres containing GM-CSF and Gag P55. The strategy of cytokine microparticles and DNA vaccines priming, followed by boosting with microparticles containing cytokine and antigen protein may prove effective in HIV DNA vaccine design.; Cotransfection of a DNA vaccine with chemokine plasmids may recruit dendritic cells (DCs) to capture the antigenic genes and their products. We investigated the effects of MIP-1α, MIP-3α, and MIP-3β plasmids (pMIP-1α, pMIP-3α, and pMIP-3β, respectively) on enhancing the immune responses to a Gag DNA vaccine (pGag). PMIP-1α and pMIP-3α were potent activators in modulating CTLs. Our studies demonstrate that co-administration of chemokine plasmids offers a valuable strategy to modulate antigen-specific immunity.; We explored the timing effect of pMIP-3α with respect to DNA vaccine. We observed that injecting the pMIP-3α 3 days before the pGag vaccine markedly increased CD8+ T cell response and the immunity was shifted towards Th1 type. To design a clinically applicable approach to enhance CTL response, a plasmid DNA delayed release system was designed employing alginate microspheres. The co-inoculation of pMIP-3α with microspheres containing pGag may lead to recruitment of immature DCs, promote pGag uptake and improve CD8+ T cell response. The delayed release system of pGag potently enhanced CD8+ T cell responses in mice compared with the co-inoculation of pGag and pMIP-3α with or without blank microspheres.; The co-inoculation of pMIP-3α, pGM-CSF and pGag, may potentially target pGag to immature DCs and activate these cells. In vaccination studies, this strategy markedly shifted the immunity towards a Th1-type and provided greater protection against a challenge with Gag encoding vaccinia virus compared to the co-inoculation of pGag with either pMIP-3α or pGM-CSF.