PATHOGENESIS OF HIV ASSOC THROMBOTIC MICROANGIOPATHY

血栓性微血管病可能是感染人类免疫缺陷病毒(HIV)患者最常见的微血管损伤形式。这种疾病的发病机制几乎一无所知，尽管它可能是内皮细胞损伤，可能是病毒感染的直接结果，是一个关键的早期事件。本研究的目的是利用血栓性微血管病变的相关动物模型来阐明趋化因子受体的表达和实质组织的病毒感染在本病发病机制中的作用。初步研究表明，当实验感染HIV2时，一定比例的猕猴会患上血栓性微血管病，这种疾病在形态上与人类艾滋病毒相关的血栓性微血管病相似，如果不完全相同的话。我们将通过临床监测血液和尿液以寻找器官功能障碍的证据、免疫异常(包括涉及淋巴细胞亚群的异常)和感染的血清学证据，来确定感染猕猴的疾病过程的时间顺序。通过定期活检和相关器官(包括心脏、肺、脑和肠道)的尸检研究，将建立形态上的相关性。对获得的组织的专门研究将包括免疫组织化学和原位杂交探针，以确定病毒和/或病毒蛋白的存在，以及这些器官内，尤其是微血管损伤部位多种趋化因子受体表达的合成。HIV-2感染灵长类动物模型为研究这一微血管疾病的发病机制提供了独特的机会。在一个特定的目标中，建议使用培养的主动脉和微血管内皮细胞进行体外研究，以进一步剖析导致血栓前状态的内皮损伤的中心介质。最后，我们建议利用从非人类灵长类动物和体外系统获得的洞察力来研究相关的人类活检组织，以评估趋化因子受体的表达和病毒感染性在人类感染HIV的微血管损伤发展中的相关性。总之，这些研究将大大提高我们对趋化因子受体实质表达在HIV相关血栓性微血管病变发病机制中的作用的理解，并为可能改善这一疾病过程的治疗干预提供可能的策略。

Thrombotic microangiopathy is probably the most common form of microvascular injury in patients infected with human immunodeficiency virus (HIV). Virtually nothing is known about the pathogenesis of this disorder, although it is likely endothelial cell injury, perhaps occurring as a direct result of viral infection, is a critical early event. The goal of the proposed studies is to utilize a relevant animal model for this thrombotic microangiopathy to delineate the role of chemokine receptor expression and viral infection of parenchymal tissues in the pathogenesis of this disease process. Preliminary studies have shown that a proportion of macaques, when experimentally infected with HIV2, will develop thrombotic microangiopathy that is morphologically similar, if not identical, to human HIV-associated thrombotic microangiopathy. We will define the chronology of this disease process in infected macaques by means of clinical monitoring of serum and urine for evidence of organ dysfunction, immunological abnormalities including those involving lymphocyte subsets, and serologic evidence of infection. Morphologic correlation will be established by periodic biopsy and by necropsy studies of relevant affected organs including heart, lung, brain, and gut. Specialized studies of the tissues obtained will include immunohistochemical and in situ hybridization probes for the presence of virus and/or viral proteins, and synthesis of expression of multiple chemokine receptors within these organs and, most specifically, at sites of microvascular injury. The HIV-2 infected primate model provides a unique opportunity to study the pathogenesis of this microvascular disease process. In one specific aim, in vitro studies using cultured aortic and microvascular endothelial cells are proposed to further dissect the central mediators of endothelial injury that lead to a pro- thrombotic state. Finally, we propose to utilize the insights gained from these studies of non-human primate and in vitro systems to studies of relevant human biopsy tissue, in order to assess the relevance of chemokine receptor expression and viral infectivity on the development of microvascular injury in humans infected with HIV. These studies, in aggregate, will substantially enhance our understanding of the role of parenchymal expression of chemokine receptors in the pathogenesis of HIV-associated thrombotic microangiopathy, and offer possible strategies for therapeutic interventions that may ameliorate this disease process.