IMMUNOPATHOGENESIS OF INTESTINAL DISEASE IN AIDS

不明原因的肠道功能障碍在HIV感染者中很常见 不管有没有艾滋病以前的研究表明， 疾病进展期间HIV抗原和RNA的表达，以及 与组织病理学改变、临床症状和 免疫改变这些变化在艾滋病毒感染者中最大 没有艾滋病。我们假设肠粘膜是首选的 艾滋病毒的储存库和淋巴细胞被感染的部位， 摧毁.这个过程是长期的，自我延续的，因为 细菌和其他外来抗原的接近以及改变的 释放调节HIV复制的细胞因子。但 该过程的致病重要性尚未明确。的目的 这项建议是为了确定艾滋病毒的细胞库和内容， 肠粘膜中的DNA和RNA，以确定粘膜中是否有HIV RNA 表达与肠道症状、组织病理学 改变和加速疾病进展。HIV的定位 细胞损伤的区域将寻求提供直接的证据， 它在肠道疾病中的作用。研究将涉及艾滋病毒感染者 有症状和无症状的志愿者和对照组， 每季度进行一次，并在两年内进行三次GI评估。蜂窝 粘膜和血液中的粘膜病毒储存库和粘膜病毒含量将被 通过RNA原位杂交、DNA和RNA模板特异性 聚合酶链反应，原位PCR，电子和免疫电子 显微镜和免疫组织学。细胞通过凋亡发生裂解，或 将鉴定出明显的合胞体形成， 通过免疫组织化学和免疫电子显微镜测定。的 选择的细胞因子和特异性抗HIV免疫的相对重要性 将比较调节粘膜HIV RNA产生的功能， HIV RNA表达的预测模型。论证 肠粘膜在疾病进展中的重要性可能导致更好的 了解淋巴耗竭的潜在机制， 导致新的治疗策略。

Unexplained intestinal dysfunction is common in HIV-infected individuals with or without AIDS. Previous studies demonstrated variation in the expression of HIV antigens and RNA during disease progression, and associations with histopathologic alterations, clinical symptoms, and immune alterations. The changes were greatest in HIV-infected individuals without AIDS. We hypothesize that intestinal mucosa is a preferred reservoir for HIV and a site where lymphocytes become infected and are destroyed. The process is chronic and self-perpetuating due to the proximity of bacterial and other foreign antigens and to the altered release of cytokines which modulate HIV replication. However, the pathogenic importance of this process is not well defined. The aims of this proposal are to determine the cellular reservoirs and content of HIV DNA and RNA in intestinal mucosa, to determine if mucosal HIV RNA expression is related to intestinal symptoms, histopathologic alterations, and accelerated disease progression. The localization of HIV to areas of cellular injury will be sought to provide direct evidence of its role in intestinal disease. Studies will involve HIV-infected volunteers with and without symptoms and controls who are followed quarterly and undergo three GI evaluations over two years. Cellular reservoirs and mucosal viral content in mucosa and blood will be determined by RNA in situ hybridization, DNA and RNA template-specific polymerase chain reaction, in situ PCR, electron and immunoelectron microscopy, and immunohistology. Cells undergoing lysis via apoptosis or apparent syncytia formation will be identified and the presence of HIV determined by immunohistochemistry and immunoelectron microscopy. The relative importance of selected cytokines and specific anti-HIV immune functions in modulating mucosal HIV RNA production will be compared and a predictive model for HIV RNA expression derived. Demonstration of the importance of intestinal mucosa in disease progression may lead to better understanding of the mechanisms underlying lymphoid depletion and could lead to new therapeutic strategies.