TLR Ligand-Based Vaccines for SIV/HIV

描述（由申请人提供）：控制全球艾滋病毒流行需要开发一种预防和治疗艾滋病毒的疫苗。一种有效的疫苗需要引起中和抗体以及有效的CTL反应。toll样受体（TLR）配体是抗原提呈细胞的有效激活剂，在成功的适应性免疫反应的发展中起着重要作用。我们假设在HIV疫苗制剂中使用合成的TLR配体，如免疫刺激DNA，将改善抗HIV免疫反应。此外，抑制tlr诱导的下调免疫应答的抑制途径，如IL-10和吲哚胺2,3-双加氧酶（IDO），应进一步优化免疫应答。因此，我们建议研究：1)基于TLR配体的模型抗原（卵清蛋白）和灭活SIV疫苗接种后记忆性CD8+ T细胞反应的发展，效应反应和中枢记忆反应的特征，以及记忆细胞发展和维持对CD4+ T细胞的需求；2)在体外和体内系统中，通过抑制IDO（一种下调T细胞反应的色氨酸分解代谢的关键酶）和/或通过中和抑制性细胞因子IL-10来增强免疫反应的能力；3)上述方法在小鼠中引发的SIV免疫反应的结果将被重建为表达TLR9的人/灵长类动物细胞表达谱；4) SIV攻击前后在体外和体内猕猴系统中SA 1-3选择的最有希望的方法；5) TLR配体疫苗在人PBMC系统中的有效性。具体而言，将通过使用来自HIV+/CMV+供者的pbmc，评估CMV+供者在TLR配体和灭活CMV孵育后CD4+和CD8+ T细胞对CMV记忆反应的增强，以及CD4耗损对抗CMV反应和抗HIV反应的影响。

DESCRIPTION (provided by applicant): Control of the worldwide HIV epidemic will require development of a preventive and therapeutic HIV vaccine. An effective vaccine will need to elicit neutralizing antibodies as well as an effective CTL response. Toll-like receptor (TLR) ligands are potent activators of antigen presenting cells that are central in the development of a successful adaptive immune response. We hypothesize that using synthetic TLR ligands, such as immunostimulatory DNA, in HIV vaccine preparations will improve anti-HIV immune responses. Furthermore, inhibiting TLR-induced inhibitory pathways that down-regulate immune responses, such as IL-10 and indoleamine 2,3-dioxygenase (IDO), should further optimize immune responses. Thus, we propose to investigate: 1) the development of memory CD8+ T cell responses after TLR ligand-based vaccination with a model antigen (ovalbumin) and with inactivated SIV, characterization of the effector and central memory responses, and requirement for CD4+ T cells in the development and maintenance of memory cells; 2) the ability to augment immune responses by inhibiting IDO, a critical enzyme in tryptophan catabolism that down-regulates T cell responses, and/or by neutralizing the inhibitory cytokine IL-10 in in vitro and in vivo systems; 3) the outcome of the approaches mentioned above to elicit immune responses against SIV in mice that will be reconstructed to express the human/primate cellular expression profile of TLR9; 4) the most promising approaches selected in SA 1-3 in an in vitro and in an in vivo macaque system before and after SIV challenge; 5) the efficacy of TLR ligand-based vaccines in a human PBMC system. Specifically, the augmentation of CD4+ and CD8+ T cell memory responses to CMV in CMV+ donors after incubation with TLR ligands and inactivated CMV will be assessed as well as the effect of CD4-depletion on the anti-CMV responses and anti-HIV responses by using PBMCs from HIV+/CMV+ donors. These experiments were designed to provide a balanced investigation that explores fundamental immunology and provides the practical aspects of vaccinology that will move us closer to development of an effective HIV vaccine for humans.