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New Strategy to Improve Gastrointestinal Health in SIV/HIV

改善 SIV/HIV 胃肠道健康的新策略

基本信息

批准号：
10437849
负责人：
CRISTIAN APETREI
金额：
$ 76.28万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437849
关键词：
AIDS prevention Acquired Immunodeficiency Syndrome Acute African African Green Monkey Aging Agreement Animals Blood Circulation CD4 Positive T Lymphocytes Characteristics Chronic Clinical Colitis Comparative Study Data Dextran Sulfate Disease Progression FDA approved Food Functional disorder Future Gastrointestinal Hemorrhage Gastrointestinal tract structure Goals Guidelines Gut Mucosa HIV HIV Infections Health Human Immune Individual Infection Inflammation Intervention Intervention Studies Intestinal Motility Intestinal Mucosa Intestinal Secretions Intestines Lead Lesion Macaca Maintenance Modeling Mucous Membrane Mus Nature Octreotide Outcome Pathogenesis Pathogenicity Pathology Peristalsis Pharmaceutical Preparations Phenotype Plant Roots Prevalence Recovery Relaxation Residual state Rest SIV Site Somatostatin Suggestion T-Cell Depletion Testing Therapeutic Therapeutic Intervention Tight Junctions Tissues Vasoactive Intestinal Peptide Virus Virus Replication antiretroviral therapy base comorbidity design experimental study gastrointestinal healing immune activation improved infection management irritation microbial mucosal site nonhuman primate novel therapeutics preservation prevent repaired restoration virtual

项目摘要

The gastrointestinal (GI) tract is the primary site of HIV replication and CD4+ T cell depletion. HIV induces major alterations at the mucosal sites, which impact their barrier function, permitting transfer of microbial products from the intestinal lumen into the surrounding tissues and into the general circulation. This microbial translocation is a key driver of the chronic immune activation and inflammation (IA/INFL) that are responsible for HIV disease progression. IA/INFL have a tremendous impact on the outcome of HIV infection, and persist even in subjects on antiretroviral therapy (ART), preventing a proper recovery of the CD4+ T cells and being responsible for comorbidities and accelerated aging. Control of chronic IA/INFL is thus one of the major goals both for prevention of HIV-associated comorbidities and for cure strategies. However, even though the impact on the GI tract mucosa appears to be central to HIV pathogenesis, approaches aimed at maintaining or repairing the mucosal barrier are lacking. One of the reasons is that mucosal irritations represented by the continuous transit of food and by digestive secretions are difficult to counterbalance and therefore the lesions persist virtually indefinitely. Our hypothesis is that interventions aimed at repairing the intestinal mucosal damage will be effective in controlling chronic IA/INFL and preventing disease progression, irrespective of the levels of viral replication. We will test three working hypothesis in three different sets of experiments: (i) a therapeutic intervention promoting intestinal health in acutely SIV-infected RMs will lead to a phenotype of viremic controllers of IA/INFL and delayed disease progression; (ii) a therapeutic intervention promoting intestinal healing in acutely SIV-infected RMs on early ART (modeling current guidelines recommending early initiation of ART) will result in a complete control of IA/INFL and in complete immune restoration at the mucosal sites; and (iii) a therapeutic intervention promoting intestinal healing in chronically SIV-infected RMs on prolonged ART (illustrative of the majority of the HIV infected individuals) will result in a complete control of IA/INFL and an improved immune restoration at the mucosal sites. For intestinal healing, we will use an FDA-approved drug (Octreotide, OCT), which (i) reduces intestinal secretions; (ii) reduces/normalizes intestinal peristalsis; (iii) decreases the release of the vasoactive intestinal peptide (VIP), thus inducing descending intestinal relaxation; (iv) reduces GI bleeding. Altogether, these effects have the potential to facilitate intestinal healing. In mice with colitis, somatostatin reduced inflammation and promoted repairs of the tight junctions, confirming the strong scientific premises of this application. Our approach will directly probe the utility of promoting intestinal healing in limiting the deleterious consequences of acute and chronic HIV infection. If successful, our study may lead to a new therapeutic paradigm aimed to preserve gut integrity and avoid disease progression and will have a tremendous impact on HIV infection management.

胃肠道（GI）是HIV复制和CD 4 + T细胞耗竭的主要部位。HIV诱导粘膜部位的重大改变，影响其屏障功能，允许微生物转移产品从肠腔进入周围组织并进入全身循环。这种微生物易位是慢性免疫激活和炎症（IA/INFL）的关键驱动因素，艾滋病的发展。IA/INFL对HIV感染的结果有巨大影响，并且持续存在即使在接受抗逆转录病毒治疗（ART）的受试者中，也会阻止CD 4 + T细胞的适当恢复，导致合并症和加速衰老。因此，控制慢性IA/INFL是主要目标之一用于预防HIV相关合并症和治疗策略。然而，尽管影响对胃肠道粘膜的影响似乎是HIV发病机制的核心，旨在维持或缺乏修复粘膜屏障的能力。其中一个原因是，食物和消化分泌物的连续运输难以平衡，因此病变几乎无限期地存在。我们的假设是，旨在修复肠粘膜的干预措施损伤将有效控制慢性IA/INFL和预防疾病进展，不管病毒复制的水平如何。我们将测试三个工作假设在三个不同的集合，实验：（i）在急性SIV感染的RM中促进肠道健康的治疗干预将导致 IA/INFL的病毒血症控制者的表型和延迟的疾病进展;（ii）治疗性干预促进急性SIV感染RM在早期ART中的肠道愈合（模拟当前指南建议早期开始ART）将导致IA/INFL的完全控制和完全免疫粘膜部位的修复;和（iii）促进慢性炎症中肠愈合的治疗性干预 SIV感染的RM接受长期ART治疗（说明大多数HIV感染者）将导致完全控制IA/INFL和改善粘膜部位的免疫恢复。对于肠道愈合，我们将使用FDA批准的药物（奥曲肽，OCT），其（i）减少肠道分泌物;（ii）减少/正常化肠水肿;（iii）减少血管活性肠肽（VIP）的释放，从而诱导下行肠道松弛;（iv）减少胃肠道出血。总之，这些影响具有促进肠道愈合的潜力。在患有结肠炎的小鼠中，生长抑素减少了炎症，紧密连接的修复，证实了这一应用的强有力的科学前提。我们的方法将直接探索促进肠道愈合在限制急性和慢性炎症的有害后果中的效用，慢性HIV感染如果成功，我们的研究可能会导致一种新的治疗模式，旨在保护肠道完整性和避免疾病进展，并将对艾滋病毒感染管理产生巨大影响。