Assessing the Role of GI Tract Damage to HIV/SIV Disease Progression

摘要 粘膜屏障完整性的改变导致肠道微生物产物移位 肠腔进入肠粘膜，然后进入大循环是致病HIV/SIV的特征 感染。艾滋病毒相关性肠病(腹泻、体重减轻、营养不良、吸收不良和绒毛萎缩) 据报道发生在大流行的早期，但胃肠道功能障碍和 艾滋病毒/SIV疾病的进展从未被确定。发展过程中涉及的途径 HIV/SIV相关的肠道功能障碍也知之甚少。在致病性艾滋病毒/SIV感染中，肠道 功能障碍发生得很早，上皮损伤和CD4+T细胞耗竭同时出现，因此 不能分离。因此，很难进行干预措施，目的是研究 HIV/SIV感染者或猕猴的粘膜损伤。相反，SIV的自然宿主(如非洲 绿色和尚(Green Monkyes，AGM)是剖析不同潜在机制相对贡献的理想模型 粘膜功能障碍，因为它们在感染过程中保持粘膜完整性，尽管水平很高 因此，在整个SIV感染过程中没有微生物易位。 此外，只有在急性SIV感染期间，粘膜中的CD4+T细胞才会在AGM中发生一过性的耗竭。 我们的首要目标是了解胃肠道功能障碍在发展为艾滋病中的作用 和非艾滋病合并症，我们设计了一套SIVsab感染的AGM的干预方法来 通过据报道影响胃肠道完整性和疾病的机制导致胃肠功能障碍 HIV感染的进展：(I)免疫细胞内稳态的改变，通过大量消耗 (2)胃肠道粘膜上皮细胞的直接损伤。我们开发了所有必要的动物模型 这项研究(加勒比地区非进行性SIV感染的AGM模型；延长的实验性模型 使用CD4R1单抗耗尽CD4+T细胞；以及通过 将葡聚糖硫酸钠(DSS)注射给未感染的猕猴和感染SIV的AGM)。我们 还开发了多种实验室工具来研究粘膜功能障碍及其在 艾滋病的发病机制。我们的具体目标是：(1)评估CD_4~+T细胞耗竭对 肠道功能障碍的发展和疾病的进展。(2)直接评估肠道影响 上皮损伤对肠道功能障碍的发展和疾病进展的影响。(3)评估以下项目的影响 CD_4~+耗竭和DSS诱导的结肠炎共同作用所致的肠道功能障碍 进步。这里提出的实验将直接评估胃肠道功能障碍对艾滋病毒的贡献。 并将调查艾滋病毒/SIV相关肠道功能障碍的一些机制。 因此，这些研究将为未来旨在保护肠道完整性和避免疾病的治疗策略提供信息 进步。

Abstract Alterations of the mucosal barrier integrity resulting in translocation of microbial products from the intestinal lumen into the gut mucosa and then into the general circulation are characteristic to pathogenic HIV/SIV infections. HIV-associated enteropathy (diarrhea, weight loss, malnutrition, malabsorption and villous atrophy) was reported to occur early in the pandemic, but a direct causative relationship between GI dysfunction and HIV/SIV disease progression has never been established. The pathways involved in the development of HIV/SIV–related gut dysfunction are poorly understood too. In pathogenic HIV/SIV infections, intestinal dysfunction occurs very early and epithelial damage and CD4+ T cell depletion arise simultaneously and thus cannot be dissociated. It is therefore difficult to perform interventions aimed at studying the mechanisms of the mucosal damage in HIV/SIV-infected humans or macaques. Conversely, natural hosts of SIVs (such as African green monkyes, AGMs) are ideal models to dissect the relative contribution of different potential mechanisms of the mucosal dysfunction, because they maintain mucosal integrity throughout infection in spite of high levels of viral replication and, as a result, microbial translocation is absent throughout the course of SIV infection. Furthermore, mucosal CD4+ T cell depletion occurs transiently in AGMs, only during acute SIV infection. Our overarching objective being to understand the role of the GI dysfunction in the progression to AIDS and non-AIDS comorbidities, we designed a set of interventional approaches in SIVsab-infected AGMs to induce gastrointestinal dysfunction through mechanisms that were reported to impact GI integrity and disease progression in HIV infection: (i) alterations of the immune cell homeostasis through massive depletion of the CD4+ T cells; (ii) direct epithelial damage of the GI mucosa. We developed all the animal models necessary for this study (the Caribbean AGM model of nonprogressive SIV infection; the model of prolonged experimental depletion of CD4+ T cells using the CD4R1 monoclonal antibody; and a model of GI epithelial damage through administration of dextran sulfate sodium (DSS) to both uninfected macaques and SIV-infected AGMs). We have also developed multiple laboratory tools for the study of the mucosal dysfunction and its role in the pathogenesis of AIDS. Our specific aims are: (1) To assess the impact of CD4+ T cell depletion on the development of gut dysfunction and disease progression. (2) To directly assess the impact of intestinal epithelial damage on the development of gut dysfunction and disease progression. (3) To assess the impact of gut dysfunction generated by the combined action of CD4+ depletion and DSS-induced colitis on disease progression. The experiments proposed here will directly assess the contribution of GI dysfunction to HIV disease progression and will investigate some of the mechanisms of the HIV/SIV-related gut dysfunction. These studies will thus inform future therapeutic strategies aimed to preserve gut integrity and avoid disease progression.