Effect of host immunity stimulated by viral IL-10-deleted RhCMV vaccines on SIV rebound

艾滋病毒在抗逆转录病毒治疗(ART)中断后的反弹通常被认为反映了 持久性蓄水池中发现长寿记忆中的CD4+T细胞，与较小的蓄水池反应迟缓 抢篮板球。然而，在ART抑制下的组织储集层的特征很差，所以我们没有 了解这些储集层的特性是否对反弹动力学有主要影响。的贡献 宿主对反弹动力学的免疫反应也知之甚少，特别是因为大多数可用数据是 专注于在急慢性疾病中产生与病毒载量控制无关的干扰素-γT细胞反应 感染。如果这种不分青红皂白的回应总数对 抢篮板球。 项目2将利用恒河猴模型的独特优势来了解组织如何 水库和宿主免疫力影响反弹。动物模型将提供频繁的纵向样本 在抑制ART期间和在反弹期间，组织驻留细胞和复发病毒的数量，这将是 由Mario Stevenson博士在Project 3的赞助下描述。此外，我们还有独特的 恒河猴利用病毒诱导Mamu-E限制性CD8+T细胞和记忆性NK细胞的能力 IL-10-缺失的RhCMV/SIV疫苗。与传统的表达Ia类的CD8+T细胞不同 干扰素-γ、1，2MAMU-E限制性CD8+T细胞可能有助于抑制甚至很快消除病毒 感染后，当SIV在T细胞中快速复制时，许多T细胞仅限于肠道组织。我们建议 人类患者在停用抗逆转录病毒药物后的情况类似于感染的早期阶段，即艾滋病毒 反弹可能是从少数细胞在有限的解剖部位重新激活病毒开始的。因此， 在某些人类患者中是否存在人类白细胞抗原-E限制性反应(项目1)或可在接种疫苗中诱导 无论是人类还是猕猴，这些个体都可能表现出延迟反弹。 我们推测，在ART条件下，RhCMV/SIV治疗性疫苗诱导的独特免疫反应， 但不是由Ad/SIV疫苗单独使用时产生的常规CTL，改变了组织病毒库和SIV 回弹动力学。我们的具体目标是：1.检验治疗性RhCMV/SIV疫苗接种是否优于Ad/SIV 为TFH驻留的SIV水库的枯竭接种疫苗。2.测试RhCMV/SIV疫苗接种是否减缓反弹 运动学。3.确定在未接种疫苗的个体中是否通过以下方式诱导了人类白细胞抗原/MAMU-E限制性T细胞反应 CMV合并感染，是延迟反弹的生物标志物。

HIV rebound after interruption of anti-retroviral therapy (ART) is generally thought to reflect the size of the persistent reservoir found in long-lived memory CD4+ T cells, with a smaller reservoir reflected in delayed rebound. However, tissue reservoirs under ART suppression have been poorly characterized, so we do not know if characteristics of those reservoirs have a dominant impact on rebound kinetics. The contribution of host immune responses to rebound kinetics is also poorly understood, especially since most available data are focused on IFN-γ producing T cell responses that are not related to control of viral load in acute or chronic infection. It would be surprising if the indiscriminate total of such responses had an important impact on rebound. Project 2 will leverage unique advantages of the rhesus macaque model to understand how tissue reservoirs and host immunity impact rebound. The animal model will provide frequent longitudinal samples of tissue-resident cells and recrudescent virus throughout suppressive ART and during rebound, which will be characterized by Dr. Mario Stevenson under the auspices of Project 3. In addition, we have the unique capability in rhesus macaques to induce both Mamu-E-restricted CD8+ T cells and memory NK cells using viral IL-10-deleted RhCMV/SIV vaccines. In contrast to conventional class Ia-restricted CD8+ T cells expressing IFN-γ,1,2 Mamu-E-restricted CD8+ T cells likely contribute to suppression and even elimination of virus soon after infection, when SIV is replicating quickly in T cells, many of which are confined to gut tissue. We propose that the situation in a human patient after ART withdrawal is similar to that early stage of infection, in that HIV rebound presumably begins from a small number of cells reactivating virus in restricted anatomic sites. Thus, if HLA-E-restricted responses are present in some human patients (Project 1) or can be induced in vaccinated humans or macaques, these individuals might exhibit delayed rebound. We hypothesize that the unique immune responses elicited by RhCMV/SIV therapeutic vaccination under ART, but not conventional CTL elicited by Ad/SIV vaccine when used alone, alter both tissue viral reservoirs and SIV rebound kinetics. Our specific aims are: 1. Test if therapeutic RhCMV/SIV vaccination is superior to Ad/SIV vaccination for depletion of the Tfh-resident SIV reservoir. 2. Test if RhCMV/SIV vaccination slows rebound kinetics. 3. Determine if HLA/Mamu-E-restricted T cell responses are induced in unvaccinated individuals by CMV co-infection and are a biomarker for delayed rebound.