Correlates of elite control of SIV

描述(由申请人提供)：“精英控制者”(ECs)是在没有治疗的情况下有效控制艾滋病毒复制的罕见个人，通过为我们提供一个定义成功的宿主免疫反应的机会，可能有助于指导艾滋病疫苗的开发。然而，不幸的是，在这些受试者中研究与控制相关的病毒学和免疫学参数是具有挑战性的。 我们已经确定了一个由13只恒河猴组成的独特的队列，它们自发地将SIVmac239的复制控制在极低的水平，最长可达5年。MHC I类等位基因Mamu-B*17存在于13个EC中的9个(69%)，而在正常进展者中只有19%，这表明该等位基因可能限制了特别有效的CD8T细胞反应。最近，我们在4个Mamu-B*17阳性的EC中瞬时耗尽了外周CD8细胞。CD8的耗尽与病毒血症的短暂增加100-10,000倍相关，随着CD8计数的反弹，病毒血症迅速减少。引人注目的是，当CD8细胞恢复时，只有一小部分Mamu-B*17限制性的、SIV特异性的CD8群体扩大到了耗尽前水平的250倍。我们推测，这一小撮CD8 T细胞反应推动了对这些动物体内SIV复制的精英控制。在这里，我们建议在体外和体内两个特定的目标来检验这一假说。 在具体目标1中，我们将构建带有Mamu-B*17表位逃逸突变的突变病毒，并在体外测试其适合性。我们还将在一个新开发的体外培养系统中测试来自ECs的表位特异性CD8细胞抑制这些逃逸变体和野生型SIVmac239生长的能力。 在具体目标2中，我们将用逃逸变异病毒挑战ECs。我们预测，逃逸突变将“敲除”表达Mamu-B*17的ECs中关键的CD8 T细胞反应，因此这些动物将无法控制这一挑战。相反，B*17阴性的ECs应该会抑制突变病毒。

DESCRIPTION (provided by applicant): "Elite controllers" (ECs), rare individuals who effectively control HIV replication in the absence of treatment, may help guide AIDS vaccine development by providing us a chance to define successful host immune responses. Unfortunately, however, it is challenging to study virological and immunological parameters associated with control in these subjects. We have identified a unique cohort of 13 rhesus macaques that spontaneously controlled SIVmac239 replication to extremely low levels for up to 5 years. The MHC class I allele Mamu-B*17 is present in 9 of 13 ECs (69%), while it occurs in just 19% of normal progressors, suggesting that this allele might restrict particularly effective CD8 T cell responses. Recently, we transiently depleted peripheral CD8 cells in 4 Mamu-B*17- positive ECs. CD8 depletion was associated with a brief 100-10,000-fold increase in viremia, which rapidly diminished as CD8 counts rebounded. Strikingly, when CD8 cells returned, only a small subset of Mamu-B*17-restricted, SIV-specific CD8 populations had expanded up to 250-fold above pre-depletion levels. We hypothesize that this handful of CD8 T cell responses drives elite control of SIV replication in these animals. Here we propose to test this hypothesis in vitro and in vivo in two specific aims. In specific aim 1, we will construct mutant viruses bearing escape mutations in Mamu-B*17 epitopes and assay their fitness in vitro. We will also test the capacity of epitope-specific CD8 cells from ECs to suppress the growth of these escape variants and wild type SIVmac239 in a newly developed in vitro culture system. In specific aim 2, we will challenge ECs with escape variant viruses. We predict that the escape mutations will "knock out" crucial CD8 T cell responses in ECs expressing Mamu-B*17, and therefore these animals will fail to control this challenge. In contrast, B*17-negative ECs should suppress the mutant virus.