Enhancing HIV vaccine efficacy by blocking regulatory T cells

描述（由申请人提供）：由于每年新感染艾滋病毒的人数超过500万，研制艾滋病毒疫苗已成为全球优先事项。一种有效的抗艾滋病毒感染疫苗应引起强烈的细胞反应和抗体反应。虽然目前有几种候选疫苗正在进行临床试验，但仍然迫切需要设计有效的艾滋病毒疫苗。该建议的目的是通过在免疫过程中短暂阻断调节性T细胞（Tregs）来增强HIV疫苗的功效。treg，也被称为抑制性T细胞，作为免疫系统的“刹车”。它们抑制免疫反应，限制免疫反应的强度。最近的研究表明，中和Treg活性可以增强免疫反应。Tregs表面表达糖皮质激素诱导的肿瘤坏死因子受体（GITR）。GITR通过其配体GITRL（在树突状细胞、巨噬细胞和B细胞上表达）与Treg结合，可以中和Treg的功能。最近的研究还表明，GITR的参与不仅可以关闭treg，还可以共同刺激传统的CD4+ T细胞。这项拨款提案的中心假设是，通过GITR信号中和Treg功能将导致疫苗诱导的T细胞和B细胞对HIV包膜抗原的反应增强。我们将通过使用双重编码HIV包膜抗原和GITRL的DNA疫苗免疫小鼠来验证这一假设。我们将通过以下两个具体目标来实现这一建议的目标。

DESCRIPTION (provided by applicant): With the incidence of over five million new HIV infections each year the development of a HIV vaccine has become a global priority. An effective vaccine against HIV infection should induce strong cellular responses as well as antibody responses. Although there are several candidate vaccines that are currently under clinical trials there is still a critical need to design efficacious HIV vaccines. The objective of this proposal is to enhance the efficacy of HIV vaccines by transiently blocking regulatory T cells (Tregs) during immunization. Tregs, also known as suppressor T cells, serve as the "brakes" of the immune system. They dampen immune responses and limit the magnitude of immune responses. Recent studies have shown that neutralization of Treg activity leads to enhanced immune responses. Tregs express on their surface, the glucocorticoid-induced tumor necrosis factor receptor (GITR). Engagement of GITR on the Tregs by its ligand, GITRL (which is expressed on dendritic cells, macrophages and B cells) neutralizes Treg function. Recent studies also show that engagement of GITR not only turns off Tregs but also co stimulates conventional CD4+ T cells. The central hypothesis of this grant proposal is that neutralizing Treg function via GITR signaling will lead to enhancement of vaccine-induced T and B cell responses to HIV envelope antigen. We will test this hypothesis by immunizing mice with DNA vaccines that dually encode both, HIV envelope antigen and GITRL. We will accomplish the goal of this proposal by pursuing the following two specific aims. Specific Aim 1: To determine the extent to which co-expression GITRL enhances T cell responses to HIV envelope glycoprotein. Specific Aim 2: To determine the extent to which co-expression GITRL enhances B cell responses to HIV envelope glycoprotein. Taken together, these studies will determine the extent to which transiently blocking Tregs during immunization, enhances T and B cell responses to HIV envelope. It is our expectation, based upon strong preliminary data, that the proposed experiments will be successful.