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，可能会发生 在没有肠道病原体和IS的感染的早期阶段 与预后不良有关。人类免疫缺陷病毒相关的发病机制 肠病的情况还不完全清楚。我们已经确定SIV感染了 恒河猴是研究艾滋病致病机制的良好动物模型 HIV感染中肠病和营养物质吸收不良的机制。 这项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 并阐明它们在SIV感染的小肠粘膜中的作用。 恒河猴肠道疾病的发展和疾病进展。这个 SIV模型为我们提供了一个获取和分析 病毒感染早期的肠道组织通过 无症状和有症状的疾病阶段。我们将确定 SIV相关小肠上皮细胞损伤机制的研究 SIV感染早期的粘膜和随后的发展 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以及免疫 肠道淋巴细胞群的失调是很重要的 在免疫监视和上皮细胞的完整性方面。这些方面的变化 人群将与肠道SIV感染有关， 上皮细胞异常的发生、临床吸收不良和 临床课程。 具体目标1：确定肠道疾病的性质和发病特征 小肠粘膜上皮细胞损伤与腺泡增生 在SIV感染过程中，并确定其在 病理和功能改变的发展。我们将测试我们的 隐窝上皮细胞损伤和/或凋亡早期假说 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症的发生 并导致空肠的病理和功能改变。 具体目标2：确定表型和功能的变化(细胞因子 在淋巴细胞中的表达和细胞毒活性)参与 肠上皮细胞的免疫监测及其在肠上皮损伤中的作用 肠病的发展和疾病的进展。我们将测试 免疫失调和功能异常的假说 肠道淋巴样细胞可在SIV感染的早期出现，并可能是一种 肠病的发生发展机制及疾病进展 动物们。 这项拟议的研究有望提供有关致病因素的重要信息。 SIV相关性肠病的发病机制对临床有价值 制定更有效的艾滋病毒相关管理战略 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.