PATHOGENESIS OF INTESTINAL DYSFUNCTION IN SIMIAN AIDS

肠道功能障碍是HIV-1感染的一个显著特征， 在没有肠道病原体的感染早期阶段， 与预后不良有关。HIV相关的机制 肠病并不完全清楚。我们已经确定SIV感染者 恒河猴是研究艾滋病致病性的极好动物模型 HIV感染中的肠病和营养吸收不良的机制。 本提案的总体目标是确定表型和 吸收上皮细胞和淋巴亚群的功能改变 在SIV感染的小肠粘膜中的作用，并阐明它们在SIV感染的小肠粘膜中的作用。 在恒河猴中发生肠病和疾病进展。的 SIV模型为我们提供了一个独特的机会， 从病毒感染的早期阶段到 疾病的无症状和有症状阶段。康贝特人将以 SIV相关的小肠上皮细胞损伤机制 粘膜在SIV感染的早期阶段和随后的发展 病理和功能变化，包括营养吸收不良。我们 将检查免疫表型和功能改变， 肠道淋巴细胞群失调， 免疫监视和上皮细胞完整性。 未来基本假设条件发生变化 人群将与肠道SIV感染有关， 上皮细胞异常、临床吸收不良和 临床过程 具体目标1：描述肠梗阻的性质和发病情况 小肠粘膜上皮细胞损伤和隐窝增生 在SIV感染的过程中，并确定其在 病理和功能改变的发展。我们将测试我们的 假设隐窝上皮细胞损伤和/或凋亡是早期 SIV感染中的事件可导致代偿性增加， 上皮细胞增殖导致隐窝增生 并导致空肠的病理和功能改变。 具体目标2：确定表型和功能（细胞因子）的变化 表达和细胞毒活性）， 肠上皮细胞的免疫监视，并检查它们在 肠病的发展和疾病进展。 我们将测试 免疫失调和功能异常假说， 肠道淋巴样细胞可在SIV感染早期出现， 肠病发展和疾病进展的机制 那些动物 这项拟议的研究有望提供有关致病性的重要信息。 SIV相关肠病的机制，这将是有价值的， 制定更有效的管理战略， 肠道功能障碍

Intestinal dysfunction, a prominent feature of HIV-1 infection, can occur in early stages of infection in the absence of enteric pathogens and is associated with poor prognosis. The mechanisms of HIV-associated enteropathy are not fully known. We have established that SIV-infected rhesus macaques are an excellent animal model of AIDS to study pathogenic mechanisms of the enteropathy and nutrient malabsorption in HIV infection. The overall objective of this proposal is to determine phenotypic and functional alterations in absorptive epithelial cells and lymphoid subsets in SIV-infected small intestinal mucosa and elucidate their role in the development of enteropathy and disease progression in rhesus macaques. The SIV model provides us with a unique opportunity to obtain and analyze intestinal tissues from early stages of viral infection through the asymptomatic and symptomatic stages of disease. We will determine the mechanisms of SIV-associated epithelial cell injury in small intestinal mucosa in the early stages of SIV infection and the subsequent development of pathologic and functional changes, including nutrient malabsorption. We will examine immunophenotypic and functional alterations and immune dysregulation in intestinal lymphoid cell populations that are important in immune surveillance and integrity of epithelia. Changes in these populations will be associated with intestinal SIV infection, the development of epithelial cell abnormalities, clinical malabsorption and clinical course. Specific aim 1: To characterize the nature and onset of intestinal epithelial cell injury and crypt hyperplasia in small intestinal mucosa during the course of SIV infection and determine its role in the development of pathologic and functional alterations. We will test our hypothesis that crypt epithelial cell injury and/or apoptosis are early events in SIV infection which can result in a compensatory increase in epithelial cell proliferation leading to development of crypt hyperplasia and resulting in pathologic and functional changes in jejunum. Specific aim 2: To determine changes in phenotype and function (cytokine expression and cytotoxic activity) in lymphoid cells involved in immunosurveillance of intestinal epithelium and examine their role in the development of enteropathy and disease progression. We will test the hypothesis that immune dysregulation and functional abnormalities in intestinal lymphoid cells can occur early in SIV infection and may be a mechanism for the development of enteropathy and disease progression in the animals. The proposed study promises to provide important information on pathogenic mechanisms of SIV-associated enteropathy that will be valuable for the development of more effective management strategies for HIV-associated intestinal dysfunction.