Musculoskeletal Project 2

项目2-项目摘要 HIV感染导致骨质流失，而抗逆转录病毒治疗（ART）反而加重了骨质流失， 男性和女性的骨折率显著增加。然而，最近的研究表明， 在绝经后感染艾滋病毒的妇女中进一步加剧，表明艾滋病毒/抗逆转录病毒疗法与 雌激素缺乏会加剧骨骼退化虽然骨质流失的程度可能会有所不同，但所有ART药物 类导致骨丢失，我们假设这是ART的间接下游效应，由 T细胞移植后与适应性免疫重新点燃相关的免疫重建和炎症事件 细胞重建我们已经证明了T细胞重建的动物模型确实会导致 显著的炎性骨丢失，与ART诱导的骨骼退化的关键特征非常相似。在这 在模型中，包括淋巴细胞和巨噬细胞在内的适应性免疫细胞分泌关键的破骨细胞生成因子。 细胞因子NF-kB配体受体激活因子（RANKL）和TNF，其驱动基础骨吸收， 骨质流失。有趣的是，绝经后骨质疏松症，女性的典型骨病， 绝经后雌激素下降，部分原因是由B和T特征的炎症状态引起的 通过适应性免疫细胞产生RANKL和TNF。虽然病因不同，因为 雌激素缺乏和HIV/ART中的骨质流失，都涉及适应性免疫的激活，导致 慢性炎症状态的发展，我们假设炎症性骨丢失之间的冲突， 与HIV/ART相关的骨质疏松可能与雌激素缺乏相关的炎性骨质流失协同作用。 这些事件可能是绝经后HIV感染妇女骨折恶化的原因，也可能预示着 在迅速老龄化的女性艾滋病毒感染者群体中，骨折的流行迫在眉睫。该SCORE赠款的项目2将研究 HIV/ART和雌激素缺乏诱导的炎症事件是否会叠加或协同 增加炎症和骨质流失。我们将采用ART和雌激素缺乏诱导的动物模型， 炎症性骨丢失，以及人类HIV+和HIV-女性的转化临床研究，以量化 HIV/ART和雌激素下降对与适应性免疫相关的骨结构和骨转换的联合作用 功能和破骨细胞生成。我们的假设，如果得到验证，将大大告知目前的理解， HIV/ART诱导的骨骼衰退与雌激素缺乏性骨丢失之间的冲突， 潜在的HIV诱导的和雌激素缺乏诱导的免疫缺陷导致骨丢失， 确定这些缺陷是累加的还是协同的，甚至是减少的。这将产生广泛的影响 艾滋病护理的未来，特别是随着人口老龄化。

Project 2-Project Summary HIV-infection causes bone loss that is paradoxically worsened by antiretroviral therapy (ART) leading to significantly increased fracture rates in men and women. However, recent studies show that fracture incidence is further exacerbated in HIV-infected women after the menopause, suggesting a collision between HIV/ART and estrogen deficiency, aggravating skeletal deterioration. While the magnitude of bone loss may vary, all ART drug classes cause bone loss and we have hypothesized that this is an indirect downstream effect of ART, driven by immune-reconstitution and inflammatory events associated with the rekindling of adaptive immunity following T cell reconstitution. We have demonstrated that an animal model of T cell reconstitution does indeed cause significant inflammatory bone loss that closely mimics key features of ART-induced skeletal deterioration. In this model, adaptive immune cells including lymphocytes and macrophages secrete the key osteoclastogenic cytokines Receptor activator of NF-kB ligand (RANKL) and TNF which drives up basal bone resorption leading to bone loss. Interestingly, postmenopausal osteoporosis, the archetypal bone disease of women, results from estrogen decline after menopause that is also driven in part, by an inflammatory state characterized by B and T cell production of RANKL and TNF by adaptive immune cells. Although the etiologies are different, because bone loss in estrogen deficiency and in HIV/ART, both involve activation of adaptive immunity leading to the development of chronic inflammatory states, we hypothesize that a collision between inflammatory bone loss associated with HIV/ART may synergize with the inflammatory bone loss associated with estrogen deficiency. Such events may account for exacerbated fracture in postmenopausal HIV-infected women and may portend a looming epidemic of fracture in the rapidly aging female HIV community. Project 2 of this SCORE grant will study whether HIV/ART- and estrogen deficiency-induced inflammatory events collide to additively or synergistically augment inflammation and bone loss. We will employ animal models of ART- and estrogen deficiency-induced inflammatory bone loss, and translational clinical studies in human HIV+ and HIV- women to quantify the combined effects of HIV/ART and estrogen decline on bone structure and turnover in relation to adaptive immune function and osteoclastogenesis. Our hypotheses, if validated, will significantly inform current understanding of the collision between HIV/ART-induced skeletal decline with that of estrogen deficiency bone loss and the underlying HIV-induced and estrogen deficiency induced immunological defects leading to bone loss and establish whether these defects are additive or synergistic, or even diminished. This will have broad implications for the future of HIV care especially as the population ages.