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.

抽象的 冠状病毒大流行目前正在进行中，并为开发有效疫苗遏制的巨大努力 目前正在制作。基于腺病毒（AD）的疫苗是临床试验中的主要疫苗，应当 预计至少一种疫苗配方将包括AD载体。这些向量以诱导而闻名 粘膜部位的免疫反应的大量激活。胃肠道（GI）是主要部位 HIV复制和CD4+ T细胞耗竭。艾滋病毒在粘膜部位引起重大变化，这影响了他们的 屏障功能，允许将微生物产物从肠道内腔转移到周围的组织中 一般循环。微生物易位是慢性免疫激活和炎症的关键驱动力 （IA/INF）负责HIV疾病进展。 IA/Infl对结果产生了巨大影响 HIV感染并持续存在于抗逆转录病毒疗法（ART）的受试者中，以防止CD4+的适当恢复 T细胞，因此负责合并症和加速衰老。改善肠道健康和控制 因此 策略。可以想象，用于SARS-COV-2在艾滋病毒患者中使用基于广告的疫苗可能 导致高水平的IA/INFR在粘膜部位，这可能会逆转ART提供的HIV控制。所以， 我们与匹兹堡大学的Andrea Gambotto博士合作，他生产了5型重组 编码抗原Sars-Cov-2 S1亚基的转基因（AD5.SARS-COV-2-S1）。我们将使用这个 SIV感染的Art抑制恒河猴（RMS）中的疫苗以诱导有效的粘膜免疫反应 到SARS-COV2，我们将监测这些反应对HIV感染的关键致病特征的影响： （a）T细胞免疫激活，特别注意粘膜位点； （b）粘膜炎症和肠道 正直; （c）微生物易位； （d）微生物组； （e）高凝性； （f）对药物代谢和 病毒抑制； （g）对病毒储层的影响。由于严重的SARS-COV-2感染不成比例地靶向 年龄较大的年轻人和老年RMS都将包括在内。我们的具体目的是测试SARS-COV的影响 2肠道功能障碍及其后果，全身免疫激活和炎症以及 关于对年轻人与旧RMS的艺术抑制的SIV感染中对艺术和病毒储层的反应。 通过直接探测AD5.SARS-COV-2 S1疫苗对HIV感染的关键参数的影响，我们 方法将评估计划中的COVID-19疫苗接种是否具有有害的HIV- 感染受试者。我们还将评估健康胃肠道粘膜对疗效的重要性 SARS-COV-2疫苗超出了HIV感染场，涵盖了所有炎症性肠病 病理。