"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

• 批准号: 10579905
• 负责人: Satya Dandekar
• 金额: $ 72.78万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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/10579905
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Allogenic; Animals; Anti-Inflammatory Agents; Antibodies; Antigen Presentation; Autologous; Automobile Driving; B-Lymphocyte Subsets; Biological Markers; Cells; Chronic; Clinical Trials; Color; Cytotoxic T-Lymphocytes; Dependovirus; Disease; Disease remission; Environment; Flow Cytometry; Gene Expression; 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-Lymphocyte; Testing; Therapeutic; Viral; Viral Load result; Viral reservoir; Virus; Virus Inhibitors; Virus Replication; adult stem cell; antiretroviral therapy; antiviral immunity; efficacy evaluation; gene network; gut microbiota; immune activation; immunoregulation; inhibitor; innovation; metabolomics; mucosal site; nonhuman primate; novel; peripheral blood; repaired; response; stem; stem cell biology; stem cell migration; stem cell therapy; stem cells; therapeutic target; tissue regeneration; tissue repair

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储存库持续存在 艾滋病病毒感染者的淋巴组织，并对艾滋病病毒的治愈构成障碍。线索可能存在于早期 HIV感染对包括肠道淋巴组织在内的次级淋巴组织和破损的致病作用 它们的结构和功能。需要新的组合方法来靶向根除病毒 被感染的细胞。此建议的R01应用程序的总体目标是调查 间充质基质/干细胞(MSC)在增强黏膜抗病毒免疫中的作用 与抗逆转录病毒治疗联合应用的病毒抑制，以及与艾滋病毒eCD4-Ig联合应用的病毒清除 和SIV抑制剂。我们建议利用SIV感染的非人灵长类艾滋病模型来研究潜在的 骨髓间充质干细胞联合eCD4-Ig或ART有效清除病毒感染细胞的治疗益处。 MSCs是一种成体干细胞，具有抗炎和免疫调节作用，并被研究为 治疗学。SIV感染恒河猴艾滋病模型中应用MSC的初步结果 显示SIV感染细胞重新分布到淋巴滤泡，并增强了抗病毒免疫。这将打开一个 通过使用MSC和一种新的有效病毒抑制剂的组合来围栏和靶向病毒的新机会， ECD4-Ig，并减少高尔特的病毒池。我们将测试系统性MSC管理将 调节SIV感染恒河猴粘膜部位的抗原提呈和增强抗病毒免疫 能更好地抑制病毒，提高免疫恢复能力。这项提议充分利用了 凭借我们在骨髓间充质干细胞生物学、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。 本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 目的1：观察MSC给药对肠道病毒清除和抗病毒黏膜免疫功能的影响 SIV感染恒河猴的淋巴组织。MSC将被注射到慢性SIV感染的动物体内，并 它对肠道淋巴组织和外周血的抗病毒粘膜免疫和病毒清除的作用将是 检查过了。AAV表达的eCD4-Ig与MSC联合给药的疗效将被检测 根除病毒阳性细胞和病毒载量。目的2：确定骨髓间充质干细胞给药对疗效的影响 ART期间和ART中断后肠道淋巴组织中的病毒抑制。感染SIV的猕猴开始 ART期间和ART中断以及病毒学、免疫学和分子分析后将接受MSC 将会被执行。建议的研究将提供一种使用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害，并诱导有效的病毒抑制和清除。