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

评估胃肠道损伤对 HIV/SIV 疾病进展的作用

• 批准号: 9922905
• 负责人: CRISTIAN APETREI
• 金额: $ 73.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922905
• 关键词: Acquired Immunodeficiency Syndrome; Acute; African; African Caribbean; African Green Monkey; Animal Model; Antibodies; Blood; Blood Circulation; Body Weight decreased; C-reactive protein; CD4 Positive T Lymphocytes; Cell Death; Cells; Characteristics; Chronic; Coagulation Process; Colitis; Development; Diarrhea; Disease Marker; Disease Progression; Environment; Epithelial; Epithelium; Functional disorder; Future; Gastrointestinal tract structure; Goals; Gut Mucosa; HIV; HIV Enteropathy; HIV Infections; Homeostasis; Human; Immune; Incidence; Individual; Infection; Inflammation; Intervention; Intestines; Laboratories; Macaca; Macaca mulatta; Malabsorption Syndromes; Malignant Neoplasms; Malnutrition; Modeling; Monoclonal Antibodies; Mucous Membrane; Opportunistic Infections; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Plasma; Production; Reporting; Role; SIV; Sodium Dextran Sulfate; System; T-Cell Depletion; Testing; Therapeutic; Therapeutic Intervention; Villous Atrophy; Viral Load result; Virus Replication; acute infection; adaptive immune response; chronic infection; comorbidity; design; dextran sulfate sodium induced colitis; experimental study; gastrointestinal; gastrointestinal epithelium; immune activation; in vivo evaluation; inflammatory disease of the intestine; intestinal epithelium; microbial; mucosal site; nonhuman primate; pandemic disease; preservation; prevent; tool

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.

抽象的 粘膜屏障完整性的改变导致肠道产物易位 流明进入肠道粘膜，然后进入一般循环中，是病原HIV/SIV的特征 感染。与HIV相关的肠病（腹泻，体重减轻，营养不良，吸收不良和绒毛萎缩） 据报道是在大流行的早期发生的，但是胃肠道功能障碍与 HIV/SIV疾病进展从未建立。发展的途径 艾滋病毒/SIV相关的肠道功能障碍也很少了解。在致病性HIV/SIV感染中 功能障碍发生很早，上皮损害，CD4+ T细胞部署出现简单，因此 因此，很难执行旨在研究研究机制的干预措施 艾滋病毒/SIV感染的人或猕猴中的粘膜损害。相反，SIV的天然寄主（例如非洲） 绿色monkyes，agms）是剖析不同潜在机制相对贡献的理想模型 粘膜功能障碍，因为它们在整个感染中保持粘膜完整性，尽管有高水平 病毒复制，因此，在整个SIV感染过程中，微生物易位不存在。 此外，仅在急性SIV感染期间，粘膜CD4+ T细胞耗竭才在AGM中瞬时发生。 我们的总体目标是了解GI功能障碍在艾滋病发展中的作用 和非AIDS合并症，我们设计了SIVSAB感染的AGM中的一套介入方法 通过据报道会影响GI完整性和疾病的机制诱导胃肠道功能障碍 艾滋病毒感染的进展：（i）通过大量耗竭来改变免疫细胞体内稳态的改变 CD4+ T细胞； （ii）胃肠道粘膜的直接上皮损伤。我们开发了所有必要的动物模型 这项研究（非进化SIV感染的加勒比海AGM模型；延长实验的模型 使用CD4R1单克隆抗体对CD4+ T细胞的耗竭；以及通过 给予未感染的猕猴和SIV感染的AGMS硫酸葡萄酸钠（DSS）。 还开发了多种实验室工具，用于研究粘膜功能障碍及其在 艾滋病的发病机理。我们的具体目的是：（1）评估CD4+ T细胞耗竭对 肠道功能障碍和疾病进展的发展。 （2）直接评估肠的影响 肠道功能障碍和疾病进展的上皮损害。 （3）评估 CD4+部署和DSS诱导的疾病结肠炎的联合作用产生的肠道功能障碍 进展。这里提出的实验将直接评估GI功能障碍对HIV的贡献 疾病进展，并将研究与HIV/SIV相关肠道功能障碍的某些机制。 因此，这些研究将为未来的理论策略提供旨在维护肠道完整性并避免疾病的策略 进展。