Enhancing HIV vaccine efficacy by blocking regulatory T cells

描述(由申请人提供)：随着每年超过500万新的艾滋病毒感染病例的发生，艾滋病毒疫苗的开发已成为全球的优先事项。一种有效的艾滋病毒感染疫苗应该引起强烈的细胞反应和抗体反应。尽管目前有几种候选疫苗正在进行临床试验，但仍迫切需要设计有效的艾滋病毒疫苗。这项建议的目的是通过在免疫期间瞬时阻断调节性T细胞(Treg)来提高艾滋病毒疫苗的效力。T细胞，也被称为抑制性T细胞，是免疫系统的“刹车”。它们会抑制免疫反应，限制免疫反应的大小。最近的研究表明，中和Treg活性会导致免疫反应增强。Treg细胞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(表达于树突状细胞、巨噬细胞和B细胞)与Treg结合，中和Treg功能。最近的研究还表明，GITR的参与不仅关闭了Tregs，而且还共同刺激了传统的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和B细胞对HIV包膜抗原的反应增强。我们将用双重编码HIV包膜抗原和GITRL的DNA疫苗免疫小鼠来检验这一假设。我们将通过追求以下两个具体目标来实现这一建议的目标。 具体目标1：确定共表达GITRL在多大程度上增强T细胞对HIV包膜糖蛋白的反应。 具体目标2：确定共表达GITRL在多大程度上增强B细胞对HIV包膜糖蛋白的反应。 综上所述，这些研究将确定在免疫过程中瞬时阻断Tregs的程度，增强T和B细胞对HIV包膜的反应。根据强有力的初步数据，我们预计拟议中的实验将取得成功。

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.