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CD4+ T细胞耗竭的主要部位。 HIV引起粘膜位点的重大变化，会影响其屏障功能，从而可以转移微生物从肠道内腔到周围组织到一般循环的产物。这个微生物易位是负责的慢性免疫激活和炎症（IA/INFR）的关键驱动力用于HIV疾病进展。 IA/INFR对艾滋病毒感染的结果产生了巨大影响，并持续存在即使在抗逆转录病毒疗法（ART）的受试者中，也可以防止CD4+ T细胞正确恢复负责合并症和加速衰老。因此，控制慢性IA/Infl是主要目标之一都用于预防与HIV相关的合并症和治疗策略。但是，即使影响在胃肠道上，粘膜似乎是HIV发病机理的核心，旨在维持或缺乏修复粘膜屏障。原因之一是，由食物的连续过境和消化分泌物很难平衡，因此病变几乎无限期地坚持。我们的假设是旨在修复肠粘膜的干预措施损害将有效控制慢性IA/INFR和预防疾病进展，无论病毒复制水平如何。我们将在三组不同的一组中测试三个工作假设实验：（i）促进急性SIV感染RMS肠道健康的治疗干预将导致 IA/Infl和延迟疾病进展的病毒控制器的表型；（ii）治疗干预促进急性SIV感染RMS的肠道愈合对早期艺术（对当前指南进行建模建议尽早开始艺术）将完全控制IA/Infl和完全免疫在粘膜部位修复；（iii）一种治疗性干预，可促进肠道愈合 SIV感染的RMS对长期艺术（大多数艾滋病毒感染的个体说明）将导致完全控制IA/Infl，并改善了粘膜部位的免疫恢复。用于肠道治疗，我们将使用经FDA批准的药物（Octreotide，Oct），（i）减少肠道分泌物；（ii）减少/归一化肠蠕动；（iii）减少了血管活性肠肽（VIP）的释放从而诱导降肠松弛；（iv）减少胃肠道出血。总共，这些效果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并促进维修紧密的连接，证实了该应用程序的强大科学前提。我们的做法意愿直接探究促进肠道愈合的效用，以限制急性和慢性艾滋病毒感染。如果成功，我们的研究可能会导致新的治疗范式，以保持肠道完整性并避免疾病进展，并将对HIV感染管理产生巨大影响。