New Strategy to Improve Gastrointestinal Health in SIV/HIV

改善 SIV/HIV 胃肠道健康的新策略

• 批准号: 10180954
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-04 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180954
• 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

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 细胞消耗的主要部位。 HIV诱发 粘膜部位发生重大改变，影响其屏障功能，从而允许微生物转移 产品从肠腔进入周围组织并进入全身循环。这种微生物 易位是导致慢性免疫激活和炎症 (IA/INFL) 的关键驱动因素 HIV疾病进展。 IA/INFL 对 HIV 感染的结果具有巨大影响，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 CD4+ T 细胞的正常恢复并被 导致并发症和加速衰老。因此，控制慢性 IA/INFL 是主要目标之一 既用于预防艾滋病毒相关合并症，又用于治疗策略。然而，尽管影响 胃肠道粘膜上的病毒似乎是艾滋病毒发病机制的核心，旨在维持或 缺乏对粘膜屏障的修复。原因之一是粘膜刺激 食物和消化分泌物的持续运输很难平衡，因此病变 实际上无限期地持续下去。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 并预防疾病进展， 与病毒复制水平无关。我们将在三组不同的组中测试三个工作假设 实验：(i) 促进急性 SIV 感染 RM 肠道健康的治疗干预将导致 IA/INFL 病毒血症控制者的表型和延迟疾病进展； (ii) 治疗干预 促进急性 SIV 感染 RM 早期 ART 的肠道愈合（模拟当前指南 建议尽早开始 ART）将导致 IA/INFL 的完全控制和完全免疫 粘膜部位的修复； (iii) 促进慢性肠道愈合的治疗干预 感染 SIV 的 RM 长期接受 ART（说明大多数 HIV 感染者）将导致 完全控制 IA/INFL 并改善粘膜部位的免疫恢复。为了肠道愈合， 我们将使用 FDA 批准的药物（奥曲肽，OCT），它 (i) 减少肠道分泌； (二) 减少/使肠道蠕动正常化； (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。总而言之，这些影响有 促进肠道愈合的潜力。在患有结肠炎的小鼠中，生长抑素可减轻炎症并促进 修复紧密连接，证实了该应用的强大科学前提。我们的方法将 直接探索促进肠道愈合在限制急性和慢性疾病的有害后果方面的效用。 慢性艾滋病毒感染。如果成功，我们的研究可能会带来一种旨在保护肠道的新治疗范式 完整性和避免疾病进展，将对艾滋病毒感染管理产生巨大影响。