MECHANISMS OF LENTIVIRAL LYMPHOID INTERSTITIAL PNEUMONIA

肺淋巴增生/浸润性疾病通常是 与儿童和成人的艾滋病毒感染有关， 在艾滋病发作之前。作为其最常见的表现，羊 绵羊慢病毒（OvLV）感染诱导淋巴间质 肺炎（LIP），与HIV相关的肺 疾病;组织病理学和淋巴细胞表型相似 .这些慢病毒还具有相似的形态、遗传组织， 在体内经历抗原变异的能力，以及对 包括肺泡巨噬细胞。因为这些 相似之处，我们建议使用OvLV模型来研究 淋巴间质性肺炎的发生发展机制 （唇）。将检验两个不相互排斥的假设： l）由MHC分子呈递慢病毒抗原诱导T细胞 增殖，和2）T细胞的募集有助于 肺浸润性疾病 为了解决第一个假设，三个 各组新生羔羊将支气管内注射OvLV或 假接种支气管肺泡液、肺淋巴液、 在急性和慢性期连续采集外周血 疾病过程的各个阶段。从这些来源收集的T细胞 来自感染前和感染后6个月的羔羊组 将进行表型分析，并分析Vbeta基因异质性和细胞因子 转录。 来自相同隔室的T细胞培养物将被 用于研究病毒抗原特异性、效应子功能和MHC类别 I和II类限制。如果发现应答的T细胞 寡克隆，如通过分析Vbeta基因库所评估的， 将检测病毒抗原在驱动T细胞扩增中的作用。 或者，如果增殖的T细胞是多克隆的，则实验 将被设计来确定病毒蛋白是否作为超抗原。 为了解决第二个假设，标记的肺淋巴T细胞的能力， 急性和慢性感染动物的细胞从 血液流入同一动物或最近感染的动物的肺部 将研究同基因双胞胎。这些实验将提供信息 在多大程度上肺募集和隔离 活化的T淋巴细胞有助于OvLV感染动物的LIP。 阐明T细胞增殖和肺损伤的机制 慢病毒感染绵羊的浸润可能导致增强的 了解HIV相关肺部疾病的发病机制， 改进诊断、治疗和预防措施。

Pulmonary lymphoproliferative/infiltrative diseases are commonly associated with HIV infection of children and adults, and they often occur prior to the onset of AIDS. As its most common manifestation, ovine lentivirus (OvLV) infection of sheep induces lymphoid interstitial pneumonia (LIP) that is remarkably similar to HIV-associated pulmonary disease; similar histopathologically and in terms of lymphocyte phenotype . These lentiviruses also share similar morphology, genetic organization, capacity to undergo antigenic variation in vivo, and tropism for macrophages, including alveolar macrophages. Because of these similarities, we propose to use the OvLV model to investigate the mechanisms of induction and progression of lymphoid interstitial pneumonia (LIP). Two hypotheses, which are not mutually exclusive, will be tested: l) that lentiviral antigens, presented by MHC molecules, induce T cell proliferation, and 2) that recruitment of T cells contributes to the pulmonary infiltrative disease. To address the first hypothesis, three groups of newborn lambs will be injected intrabronchially with OvLV or sham-inoculated. T lymphocytes from broncho-alveolar fluid, lung lymph, and peripheral blood will be collected serially during acute and chronic stages of the disease process. The T cells collected from these sources from groups of lambs prior to infection and up to 6 months after infection will be phenotyped and analyzed for Vbeta gene heterogeneity and cytokine transcription. Cultures of T cells from the same compartments will be used to study viral antigen specificity, effector function, and MHC class I and class II restriction. If responding T cells are found to be oligoclonal, as assessed by analysis of the Vbeta gene repertoire, the role of viral antigens in driving T cell expansion will be examined. Alternatively, if the proliferating T cells are polyclonal, experiments will be designed to ascertain whether viral proteins act as superantigens. To address the second hypothesis, the capacity of labelled lung lymph T cells from acutely and chronically-infected animals to migrate from the bloodstream into the lung of the same animal or a recently-infected syngeneic twin will be studied. These experiments will provide information on the extent to which pulmonary recruitment and sequestration of activated T lymphocytes contributes to LIP in OvLV-infected animals. Elucidation of the mechanisms of T cell proliferation and pulmonary infiltration in lentivirus-infected sheep may lead to enhanced understanding of the pathogenesis of HIV-associated pulmonary disease and improved measures for its diagnosis, treatment and prevention.