Therapeutic vaccination targeting SIV viral reservoirs

 描述：艾滋病毒研究中的一个主要挑战是开发根除或治愈既定感染的治疗方法。免疫治疗是利用免疫系统靶向感染细胞的一种方式；然而，这会受到T细胞功能障碍或衰竭的阻碍。我们发现了一种新的治疗性疫苗接种策略，可以逆转已建立的T细胞对自身抗原的耐受和衰竭，以及在慢性小鼠病毒感染期间导致 出现数量极多的抗病毒CD8T细胞。这一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恒河猴暴露在这个治疗性疫苗接种平台中时，这会导致SIV特异性T细胞功能的极大增强。我们建议在此严格测试在SIV感染和抗逆转录病毒治疗(ART)期间进行抗原特异性治疗性疫苗接种可以在SIV CD8 T细胞群中诱导巨大变化，然后在ART移除后影响和控制病毒复发和病毒库的概念。潜在的假设是CTL反应的数量、位置和功能的组合，以及ART导致的靶细胞减少，是结果的主要决定因素。在R21阶段，将在接种过程中评估SIV特异性CD8T细胞的数量、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。如果达到了概述的里程碑，R33阶段将在R21阶段看到的阳性结果的基础上扩大，还将计数组织中SIV特异的T细胞，它们与SIV细胞的关系，并确定额外的增强事件是否可以提供更好的疗效。如果我们的战略成功，我们将致力于将这种类型的治疗性疫苗接种平台转化为用于艾滋病毒感染者。

 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.