CD8 T Cell Interaction with Bone Cells in HIV Disease

描述(由申请人提供)：临床研究已证明慢性免疫激活和骨质疏松症之间经常存在联系。然而，这一领域的研究尚未应用于艾滋病毒疾病，可以说，这是长期慢性免疫激活的典型临床例子。在HIV疾病中，CD8 T细胞受到慢性刺激，最终导致复制性衰老。事实上，在HIV感染者中，超过65%的CD8T细胞亚群由具有复制衰老特征的细胞组成。 老年人的骨质疏松性骨折与高比例细胞的存在有关，这些细胞具有复制衰老的标志。同样，感染艾滋病毒的人也有骨骼变化的报道，但慢性T细胞刺激与抗逆转录病毒治疗的相对贡献尚不清楚。这项拟议研究的目标是开始剖析这些临床非因果关系背后的机制。这种独特的细胞培养系统导致了对衰老的CD8 T细胞在与HIV疾病相关的免疫缺陷中的作用的早期洞察，将被用来解决复制衰老在骨骼动态平衡中的作用。这种培养系统在体内的相关性得到了体外培养的终末衰老细胞与老年人和感染艾滋病毒的年轻人中存在的某些类型的CD8T细胞之间许多表型和功能上的相似性的支持。 本研究的具体目的如下：(1)分析衰老的CD8 T细胞对骨吸收细胞破骨细胞的影响。这些实验使用从健康个体建立的同种异体抗原特异性细胞培养，也将研究脂质氧化产物在调节CD8 T细胞/破骨细胞活性中的潜在作用。(2)分析CD8 T细胞复制衰老对成骨细胞分化和成骨细胞活性的影响。在目标1中建立的培养物将用于这些实验。 拟议的发育研究代表了探索衰老的CD8 T细胞与骨破坏和骨形成作为HIV疾病发病机制的一个组成部分的潜在相互作用的初步阶段。艾滋病毒感染者长期存活率的提高进一步加强了这项研究的意义，这是一个积极的结果，但最终将导致更多人的骨骼已经受到正常衰老过程的影响。

DESCRIPTION (provided by applicant): Clinical studies have documented the frequent association between chronic immune activation and osteoporosis. However, research in this area has not yet been applied to HIV disease, which, arguably, represents the quintessential clinical example of prolonged chronic immune activation. In HIV disease, CD8 T cells are subject to chronic stimulation, ultimately leading to replicative senescence. In fact, more than 65% of the CD8 T cell subset in HIV-infected persons consists of cells with characteristics suggestive of replicative senescence. Osteoporotic fractures in the elderly are associated with the presence of high proportions of cells with markers of replicative senescence. Similarly, bone changes have been reported in persons infected with HIV, but the relative contribution of chronic T cell stimulation versus anti-retroviral therapy is unknown. The goal of the proposed research is to begin to dissect the mechanisms underlying these clinical non-causal correlations. The unique cell culture system that has led to earlier insights on the role of senescent CD8 T cells in immune deficits associated with HIV disease will be exploited to address the role of replicative senescence in bone homeostasis. The in vivo relevance of this culture system is supported by the numerous phenotypic and functional similarities between the end-stage senescent ceils that are arise in vitro, and certain types of CD8 T cells present in the elderly and in younger persons infected with HIV. The following are the specific aims of the proposed research: (1) To analyze the effects of senescent CD8 T cells on osteoclasts, the bone-resorbing cells. These experiments, using alloantigen-specific cell cultures established from healthy individuals, will also address the potential role of lipid oxidation products in the regulation of CD8 T cell/osteoclast activity. (2) To analyze the effects of CD8 T cell replicative senescence on osteoblastic differentiation and activity of osteoprogenitor cells. The cultures established in Aim 1 will be used for these experiments. The proposed developmental studies represent the initial stage in the exploration of the potential interaction of senescent CD8 T cells with the pathways of bone destruction and bone formation as a component of HIV disease pathogenesis. The significance of this research is further enhanced by the increased long-term survival of HIV-infected persons, a positive outcome, but one which will ultimately result in larger numbers of persons whose bones are already affected by the normal aging process.