Therapeutic vaccination targeting SIV viral reservoirs

针对 SIV 病毒库的治疗性疫苗接种

• 批准号: 8842310
• 负责人: VAIVA D VEZYS
• 金额: $ 24.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8842310
• 关键词: Affect; Anatomy; Animals; Anti-Retroviral Agents; Antigens; Autoantigens; Biomedical Research; CD8B1 gene; Cell Count; Cells; Chronic; Coupled; Detection; Event; Excision; Functional disorder; Gagging; Goals; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunotherapy; Individual; Infection; Intervention; Location; Macaca mulatta; Mediating; Methods; Monitor; Mus; Organ; Outcome; Patients; Phase; Phenotype; Population; Prevention; Proteins; Recrudescences; Regulatory Pathway; Research; SIV; Source; T cell response; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Translations; Vaccinated; Vaccination; Vaccines; Viral; Viral Load result; Virus Diseases; Whole Organism; Withdrawal; exhaustion; meetings; nonhuman primate; novel therapeutics; prophylactic; public health relevance; response; therapy development; vaccination strategy

 DESCRIPTION: A major challenge in HIV research is the development of therapies to eradicate or cure established infection. Immunotherapy is one way of harnessing the immune system to target infected cells; however, this is hampered by T cell dysfunction or exhaustion. We have discovered a novel therapeutic vaccination strategy that reverses established T cell tolerance and exhaustion to self-antigen, as well as during a chronic murine viral infection resulting in the emergence of extremely large numbers of anti-viral CD8 T cells. This strategy does not rely on interfering with immune regulatory pathways and is antigen-specific, leading to expansion only of targeted T cells, while maintaining normal immune homeostasis. When SIV+ Rhesus macaques are exposed to this therapeutic vaccination platform, this results in a very large augmentation of functional SIV- specific T cells. We propose here to rigorously test the concept that antigen-specific therapeutic vaccination during established SIV infection and anti-retroviral therapy (ART) can induce large changes within the SIV+ CD8 T cell population, which can then affect and control viral recrudescence and viral reservoirs after ART removal. The underlying hypothesis is that the combination of numbers, location and function of the CTL response, along with a reduction in target cells due to ART, is the principal determinant of outcome. During the R21 phase, SIV-specific CD8 T cell numbers, phenotype and function will be evaluated during the course of vaccination. SIV viral loads will also be monitored and the effects of therapeutic vaccination on viral recrudescence will be evaluated. If outlined milestones are met, the R33 phase will expand on the positive outcome seen during the R21 phase, and also enumerate SIV-specific T cells in tissues, their relation to SIV+ cells and determine whether additional boosting events can afford greater efficacy. If our strategy is successful, we will aim to translat this type of therapeutic vaccination platform for use in HIV infected individuals.

 HIV研究的一个主要挑战是开发根除或治愈已建立感染的疗法。免疫疗法是利用免疫系统靶向受感染细胞的一种方法;然而，这受到T细胞功能障碍或衰竭的阻碍。我们已经发现了一种新的治疗性疫苗接种策略，该策略逆转了已建立的T细胞耐受性和对自身抗原的耗竭，以及在慢性鼠病毒感染期间， 大量的抗病毒CD 8 T细胞的出现。这种策略不依赖于干扰免疫调节途径，并且是抗原特异性的，仅导致靶向T细胞的扩增，同时维持正常的免疫稳态。当SIV+恒河猴暴露于这种治疗性疫苗接种平台时，这导致功能性SIV特异性T细胞的非常大的增加。我们建议在此严格测试这一概念，即在已建立的SIV感染和抗逆转录病毒治疗（ART）期间，抗原特异性治疗性疫苗接种可诱导SIV+ CD 8 T细胞群内的巨大变化，从而影响和控制ART去除后的病毒复发和病毒储库。潜在的假设是CTL应答的数量、位置和功能的组合，沿着由于ART导致的靶细胞减少，是结果的主要决定因素。在R21期，将在疫苗接种过程中评价SIV特异性CD 8 T细胞数量、表型和功能。还将监测SIV病毒载量，并评估治疗性疫苗接种对病毒复发的影响。如果达到了所述的里程碑，R33阶段将在R21阶段期间观察到的阳性结果的基础上扩大，并且还计数组织中的SIV特异性T细胞，它们与SIV+细胞的关系，并确定额外的加强事件是否可以提供更大的功效。如果我们的策略成功，我们将致力于推广这种治疗性疫苗接种平台，用于艾滋病毒感染者。