"Corral and Kill" strategy for HIV eradication using MSC in an SIV model

在 SIV 模型中使用 MSC 根除 HIV 的“围堵和杀死”策略

基本信息

批准号：
10023879
负责人：
Satya Dandekar
金额：
$ 76.3万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-23 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10023879
关键词：
Acquired Immunodeficiency Syndrome Allogenic Animals Anti-Inflammatory Agents Antibodies Antigen Presentation Antiviral Agents Autologous Automobile Driving B-Lymphocyte Subsets Biological Markers Cells Chronic Clinical Trials Cytotoxic T-Lymphocytes Dependovirus Disease Disease remission Environment Flow Cytometry Gene Expression Genes Gut Mucosa Gut associated lymphoid tissue HIV HIV Infections Human Immune Immune response Immunity Immunologics Immunology Impairment Individual Inflammation Inflammatory Injury Interruption Lead Lymphoid Follicle Lymphoid Tissue Macaca Macaca mulatta Measures Mediating Mesenchymal Modeling Molecular Molecular Analysis Mucosal Immunity Mucous Membrane Pathogenicity Patients Quantitative Reverse Transcriptase PCR Recovery SIV Site Stem cell transplant Stromal Cells Structure T Virus T-Lymphocyte Testing Therapeutic Viral Viral Load result Viral reservoir Virus Virus Inhibitors Virus Replication adult stem cell antiretroviral therapy antiviral immunity gut microbiota immune activation immunoregulation inhibitor/antagonist innovation metabolomics mucosal site nonhuman primate novel peripheral blood repaired response simian human immunodeficiency virus stem stem cell biology stem cell therapy stem cells therapeutic target tissue regeneration tissue repair virology

项目摘要

Despite the presence of HIV-specific cytotoxic T cells and virus-specific antibodies, HIV reservoirs persist in lymphoid tissues in HIV infected individuals and pose obstacles for HIV cure. Clues may lie in the early pathogenic effects of HIV infection in the secondary lymphoid tissues including gut lymphoid tissue and disruption of their structure and function. Novel combination approaches are needed for targeting eradication of virally infected cells. The overall objective of this proposed R01 application is to investigate the potential of mesenchymal stromal/stem cells (MSC) in enhancing mucosal anti-viral immunity and to determine efficacy of viral suppression in combination with ART as well as the viral clearance in combination with eCD4-Ig, an HIV and SIV inhibitor. We propose to utilize SIV infected non-human primate model of AIDS to investigate potential therapeutic benefits of MSCs in combination with eCD4-Ig or ART for effective clearance of virally infected cells. MSCs are adult stem cells that are anti-inflammatory and immunomodulatory and are investigated as therapeutics. Our preliminary results of MSC administration in SIV infected rhesus macaque model of AIDS showed redistribution of SIV infected cells to lymphoid follicles and enhanced anti-viral immunity. This opens a new opportunity to corral and target the virus by using a combination of MSC and a novel potent viral inhibitor, eCD4-Ig and reduce the viral pool from GALT. We will test the hypothesis that systemic MSC administration will modulate antigen presentation and enhance anti-viral immunity at mucosal sites in SIV infected rhesus macaque model of AIDS and lead to better viral suppression and increased immune recovery. This proposal leverages on our unique strengths in MSC biology, SIV model of AIDS, mucosal immunology and novel eCD4-Ig inhibitor. The overall objective of this R01 proposal is to investigate the effects of MSC administration on anti-viral mucosal immunity and viral clearance in gut lymphoid tissue of SIV infected rhesus macaques. Aim 1: To determine the effect of MSC administration on anti-viral mucosal immunity and viral clearance in gut lymphoid tissue of SIV infected rhesus macaques. MSC will be injected into chronically SIV infected animals and its effect on anti-viral mucosal immunity and viral clearance in gut lymphoid tissue and peripheral blood will be examined. Efficacy of AAV-expressed eCD4-Ig in combination with MSC administration will be examined for eradicating virus-positive cells and viral loads. Aim 2: To determine the effect of MSC administration on effective viral suppression in gut lymphoid tissue during ART as well as after ART interruption. SIV infected macaques on ART will receive MSC during ART and after ART interruption and virologic, immunologic and molecular analyses will be performed. The proposed study will provide an innovative approach of using MSC to enhance anti-viral immunity, resolve virus-associated mucosal damage and induce effective viral suppression and clearance.

尽管存在 HIV 特异性细胞毒性 T 细胞和病毒特异性抗体，但 HIV 储存库仍然存在 HIV感染者的淋巴组织对HIV治疗构成障碍。线索可能就在早期 HIV 感染对次级淋巴组织（包括肠道淋巴组织）的致病作用和破坏它们的结构和功能。需要新的组合方法来靶向消灭病毒被感染的细胞。拟议的 R01 应用程序的总体目标是研究间充质基质/干细胞（MSC）增强粘膜抗病毒免疫并确定其功效与 ART 相结合的病毒抑制以及与 eCD4-Ig（一种 HIV）相结合的病毒清除和SIV抑制剂。我们建议利用感染 SIV 的非人灵长类艾滋病模型来研究潜在的 MSC 与 eCD4-Ig 或 ART 结合使用可有效清除病毒感染细胞，具有治疗功效。 MSC 是具有抗炎和免疫调节作用的成体干细胞，其研究目的是疗法。我们在感染SIV的恒河猴艾滋病模型中使用MSC的初步结果显示 SIV 感染细胞重新分布到淋巴滤泡并增强抗病毒免疫力。这将打开一个通过使用 MSC 和新型有效病毒抑制剂的组合来围堵和靶向病毒的新机会， eCD4-Ig 并减少来自 GALT 的病毒库。我们将检验系统性 MSC 给药会影响这一假设调节 SIV 感染恒河猴粘膜部位的抗原呈递并增强抗病毒免疫力艾滋病模型并导致更好的病毒抑制和增强的免疫恢复。该提案利用了凭借我们在 MSC 生物学、艾滋病 SIV 模型、粘膜免疫学和新型 eCD4-Ig 抑制剂方面的独特优势。该 R01 提案的总体目标是研究 MSC 给药对抗病毒粘膜的影响 SIV 感染恒河猴肠道淋巴组织的免疫和病毒清除。目标 1：确定 MSC 给药对肠道抗病毒粘膜免疫和病毒清除的影响感染 SIV 的恒河猴的淋巴组织。 MSC 将被注射到长期感染 SIV 的动物体内其对抗病毒粘膜免疫以及肠道淋巴组织和外周血中病毒清除的影响将是检查了。将检查 AAV 表达的 eCD4-Ig 与 MSC 给药相结合的功效消除病毒阳性细胞和病毒载量。目标 2：确定 MSC 给药对有效 ART 期间以及 ART 中断后肠道淋巴组织中的病毒抑制。感染 SIV 的猕猴 ART 将在 ART 期间和 ART 中断后接受 MSC 以及病毒学、免疫学和分子分析将被执行。拟议的研究将提供一种利用 MSC 增强抗病毒能力的创新方法免疫，解决病毒相关的粘膜损伤并诱导有效的病毒抑制和清除。