CTL-Mediated Elimination of Replication Competent vs. Defective HIV Proviruses from Natural Latent Reservoirs: Roles of Antigen Specificity and Functional Characteristics

尽管现代疗法改善了艾滋病毒/艾滋病患者的前景 (PLWHA)他们无法治愈感染，让这些人背负着 终身致力于昂贵的抗逆转录病毒药物。也很明显， 这些治疗不能完全恢复健康，也不能解决负面的社会问题 与艾滋病毒呈阳性相关的问题。开发一种安全有效的艾滋病毒 因此，治愈将极大地改善PLWHA的生活。治愈艾滋病毒的主要障碍 感染是一种隐藏的或“潜伏的”病毒蓄水池的建立，这种病毒可以逃避 如果一个人停止抗逆转录病毒治疗，可能会重新传播感染。 目前正在努力试图清除这些艾滋病毒宿主。从理论上讲 可以通过组合能够暴露隐藏的延迟反转剂(LRA)来实现 具有免疫效应器的病毒，如杀伤T细胞，然后可以消除这些细胞， 所谓的‘震慑和杀戮’的方法。震慑和杀戮策略的可行性是 由使用潜伏期细胞系模型的体外实验支持，其中组合 使用具有杀伤T细胞的LRA可以减少HIV病毒的蓄积量。然而，临床试验已经 试图在体内实现这一点的结果令人失望。在预赛中 研究中，我们试图通过确定LRA的组合是否 使用杀伤性T细胞可以在体外从患者的CD4T细胞样本中消除HIV。我们做了 令人惊讶的是，这一直导致了 构成艾滋病毒DNA大部分的有缺陷的艾滋病毒前病毒，而不会影响 原封不动的可诱导前病毒，需要消除才能治愈感染。在当前 我们的项目建议测试不同组合的HIV特异性杀伤T细胞和 LRA在这种测试中，希望确定能够更多地 有效地瞄准完整的诱导性前病毒。我们的研究设计将使我们能够识别 与有效相关的杀伤T细胞和LRAs的一般特征 消除完整的诱导性前病毒。在扰乱这些天然艾滋病毒的过程中 水库，我们还将测试广泛的水库测量化验，以确定 最好地反映了完整的可诱导前驱体相对于总/缺陷的耗竭 前病毒。因此，我们的研究将为设计提供关键的指导 未来临床试验中旨在治愈艾滋病毒感染的干预措施，并用于选择 以及在这些研究中使用的储层测量分析的解释。

Although modern therapies have improved the outlooks for people living with HIV/AIDS (PLWHA) they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to expensive antiretroviral medication. It has also become clear that these treatments do not fully restore health, nor do they address the negative social issues associated with being HIV positive. The development of a safe and effective HIV cure would thus greatly improve the lives of PLWHA. A major obstacle to curing HIV infection is the establishment of reservoirs of hidden or ‘latent’ virus which evade the immune system and can re-seed infection if an individual stops antiretroviral therapy. Efforts are underway to attempt to purge these HIV reservoirs. There is theoretically achievable by combining ‘latency reversing agents’ (LRAs) capable of exposing hidden virus with immune effectors such as killer T-cells that can then eliminate these cells, the so-called ‘shock and kill’ approach. The viability of the shock and kill strategy is supported by in vitro experiments using cell line models of latency, where combinations of LRAs with killer T-cells can reduce HIV reservoirs. However, clinical trials that have attempted to achieve this in vivo have yielded disappointing results. In preliminary studies, we have attempted to bridge this gap by determining if combinations of LRAs with killer T-cells could eliminate HIV from patient CD4+ T-cell samples in vitro. We made the surprising observation that this consistently resulted in the elimination of the defective HIV proviruses that make up the majority of HIV DNA, without impacting the intact inducible proviruses that need to be eliminated to cure infection. In the current project we propose the testing of different combinations of HIV-specific killer T-cells and LRAs in this assay, in the hopes of identifying combinations that are able to more effectively target intact inducible proviruses. Our study design will allow us to identify general features of both killer T-cells and of LRAs that are associated with effective elimination of intact inducible proviruses. In the process of perturbing these natural HIV reservoirs, we will also test a wide range of reservoir measurement assays to determine which best reflect depletions in intact inducible proviruses versus of total/defective proviruses. Our study will thus provide critical guidance both for the design of interventions aimed at curing HIV infection in future clinical trials, and for the selection and interpretation of reservoir measurement assays to be used in these studies.