"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特异性的细胞毒性T细胞和病毒特异性抗体，但HIV储量仍在 艾滋病毒感染个体中的淋巴组织，构成HIV治疗的障碍。线索可能会在早期 HIV感染在次生淋巴组织中的致病作用，包括肠道淋巴组织和破坏 它们的结构和功能。需要新颖的组合方法来靶向消除病毒 感染细胞。该提出的R01应用的总体目的是研究 间充质基质/干细胞（MSC）增强粘膜抗病毒免疫并确定 病毒抑制与ART结合以及病毒清除率与ECD4-Ig（HIV）结合 和SIV抑制剂。我们建议利用SIV感染的非人类灵长类动物艾滋病模型来研究潜力 MSC与ECD4-Ig或ART结合使用的治疗益处，可有效清除病毒感染的细胞。 MSC是抗炎和免疫调节的成年干细胞，被研究为 疗法。我们在SIV感染艾滋病的恒河猴模型中的MSC给药的初步结果 显示SIV感染细胞重新分布在淋巴卵泡和抗病毒免疫力上。这打开了 通过使用MSC和一种新型有效病毒抑制剂的组合来围绕和靶向病毒的新机会， ECD4-Ig并从Galt减少病毒池。我们将检验以下假设，即系统MSC给药将 调节抗原表现并增强SIV感染恒河猕猴的粘膜部位的抗病毒免疫力 艾滋病模型，导致更好的病毒抑制和增加的免疫恢复。该提议利用 关于我们在MSC生物学，SIV艾滋病模型，粘膜免疫学和新型ECD4-IG抑制剂方面的独特优势。 该R01提案的总体目的是研究MSC给药对抗病毒粘膜的影响 SIV感染恒河猴的肠道淋巴组织中的免疫和病毒清除。 目的1：确定MSC给药对肠道抗病毒粘膜免疫和病毒清除的影响 SIV感染恒河猕猴的淋巴组织。 MSC将注入长期感染的动物，并将其注入 它对肠道淋巴组织和外周血中抗病毒粘膜免疫和病毒清除率的影响将是 检查。将检查表达AAV表达的ECD4-Ig与MSC给药的功效的功效 消除病毒阳性细胞和病毒负荷。目标2：确定MSC给药对有效的影响 在艺术期间和艺术中断后，肠道淋巴组织中的病毒抑制。 SIV感染了猕猴 ART将在ART和ART中断和病毒学，免疫和分子分析后获得MSC 将执行。拟议的研究将提供一种使用MSC增强抗病毒的创新方法 免疫，解决与病毒相关的粘膜损伤并诱导有效的病毒抑制和清除率。