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: 10426962
• 负责人: CRISTIAN APETREI
• 金额: $ 69.02万
• 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/10426962
• 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

Abstract A coronavirus pandemic is currently in progress and a tremendous effort for developing effective vaccines to curb it is currently being made. Adenovirus (Ad)-based vaccines are in the lead in the clinical trials, and it is to be expected that at least one vaccine formulation will comprise of an Ad vector. These vectors are known for inducing massive activation of the immune responses at the mucosal sites. 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 general circulation. 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 thus being responsible for comorbidities and accelerated aging. Improving gut health and controlling chronic IA/INFL is thus one of the major goals both for prevention of HIV-associated comorbidities and for cure strategies. It is conceivable that the use of Ad-based vaccines for the SARS-CoV-2 in people living with HIV may result in high levels of IA/INFL at the mucosal sites, which may reverse HIV control provided by ART. Therefore, we teamedwith Dr. Andrea Gambotto from the University of Pittsburgh, who produced a recombinant type 5 Ad vector encoding the transgene for the antigen SARS-CoV-2 S1 subunit (Ad5.SARS-CoV-2-S1). We will use this vaccine in SIV-infected, ART-suppressed rhesus macaques (RMs) to induce effective mucosal immune responses to SARS-CoV2, and we will monitor the impact of these responses on the key pathogenic features of HIV infection: (a) T-cell immune activation, with particular attention given to the mucosal sites; (b) mucosal inflammation and gut integrity; (c) microbial translocation; (d) microbiome; (e) hypercoagulability; (f) impact on the drug metabolism and viral suppression; (g) impact on the viral reservoirs. Since severe SARS-CoV-2 infection disproportionately target older individuals, both young and old RMs will be included. Our specific aim is to test the impact of a SARS-CoV- 2 vaccine on the gut dysfunction and its consequences, systemic immune activation and inflammation and on the response to ART and viral reservoirs in ART-suppressed SIV infection of young versus old RMs. By directly probing the impact of an Ad5.SARS-CoV-2 S1 vaccine on key parameters of HIV infection, our approach will assess whether the planned COVID-19 vaccination has the potential of being deleterious to HIV- infected subjects. We will also assess the importance of a healthy gastrointestinal mucosa to the efficacy of the SARS-CoV-2 vaccine, which goes beyond the HIV infection field, covering all the inflammatory bowel disease pathology.

摘要 冠状病毒大流行目前正在进行中，开发有效疫苗以遏制 目前正在制定。基于腺病毒（Ad）的疫苗在临床试验中处于领先地位， 预期至少一种疫苗制剂将包含Ad载体。这些载体已知用于诱导 粘膜部位的免疫反应被大量激活。胃肠道（GI）是主要部位 HIV复制和CD 4 + T细胞耗竭。HIV在粘膜部位引起重大改变，这影响了它们的免疫功能。 屏障功能，允许微生物产物从肠腔转移到周围组织， 总循环微生物移位是慢性免疫激活和炎症的关键驱动因素 (IA/INFL），负责HIV疾病的进展。IA/INFL对结果有巨大的影响， HIV感染，即使在接受抗逆转录病毒治疗（ART）的受试者中也持续存在，阻止了CD 4+的适当恢复 T细胞，从而负责合并症和加速老化。改善肠道健康和控制 因此，慢性IA/INFL是预防HIV相关合并症和治疗的主要目标之一 战略布局可以想象，在艾滋病病毒感染者中使用基于广告的SARS-CoV-2疫苗可能会 导致粘膜部位高水平的IA/INFL，这可能逆转ART提供的HIV控制。因此， 我们与匹兹堡大学的Andrea Gambotto博士合作， 编码抗原SARS-CoV-2 S1亚基的转基因的载体（Ad 5.SARS-CoV-2-S1）。我们将使用这个 在SIV感染、ART抑制的恒河猴（RM）中接种疫苗，以诱导有效的粘膜免疫反应 我们将监测这些应对措施对艾滋病毒感染的主要致病特征的影响： (a)T-细胞免疫活化，特别关注粘膜部位;（B）粘膜炎症和肠 完整性;（c）微生物易位;（d）微生物组;（e）高凝状态;（f）对药物代谢的影响， 病毒抑制;（g）对病毒储库的影响。由于严重的SARS-CoV-2感染不成比例地针对 老年人，包括年轻和老年RM。我们的具体目标是测试SARS冠状病毒的影响， 2.疫苗对肠道功能障碍及其后果、全身免疫激活和炎症的影响 年轻与老年RM对ART和ART抑制SIV感染的病毒储库的反应。 通过直接探索Ad 5.SARS-CoV-2 S1疫苗对HIV感染关键参数的影响，我们 该方法将评估计划中的COVID-19疫苗接种是否有可能对艾滋病毒有害- 受感染的受试者。我们还将评估健康的胃肠道粘膜对治疗效果的重要性。 SARS-CoV-2疫苗，它超越了HIV感染领域，覆盖了所有炎症性肠病 病理