Therapeutic vaccination targeting SIV viral reservoirs

针对 SIV 病毒库的治疗性疫苗接种

基本信息

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
项目类别：
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

项目摘要

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.

描述：HIV 研究的一个主要挑战是开发根除或治愈已发生感染的疗法，这是利用免疫系统靶向受感染细胞的一种方法；然而，我们发现了一种阻碍 T 细胞功能障碍或衰竭的方法。新颖的治疗性疫苗接种策略，可逆转已建立的 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导致当 SIV+ 恒河猴处于正常状态时，会出现大量抗病毒 CD8 T 细胞，并且具有抗原特异性，从而仅导致目标 T 细胞的扩增。暴露于这种治疗性疫苗接种平台，这会导致功能性 SIV 特异性 T 细胞的大量增加，我们在此建议严格测试在已建立的 SIV 感染和抗逆转录病毒治疗期间进行抗原特异性治疗性疫苗接种的概念。 (ART) 可以诱导 SIV+ CD8 T 细胞群发生巨大变化，从而影响和控制 ART 去除后的病毒复发和病毒储存库。潜在的假设是 CTL 反应的数量、位置和功能的组合，以及 CTL 反应的发生。 ART 导致的靶细胞减少是结果的主要决定因素。在 R21 阶段，还将在疫苗接种过程中评估 SIV 特异性 CD8 T 细胞数量、表型和功能，并监测 SIV 病毒载量。的影响如果达到了概述的里程碑，将评估治疗性疫苗接种对病毒复发的影响，R33 阶段将扩展 R21 阶段所见的积极结果，并列举组织中的 SIV 特异性 T 细胞、它们与 SIV+ 细胞的关系，并确定是否需要额外的治疗。如果我们的策略成功，我们将致力于将这种治疗性疫苗接种平台用于艾滋病毒感染者。