Programming Dendritic Cells to Expose the Persistent HIV-1 Latent Reservoir for Immune Targeting

项目摘要/摘要 虽然目前治疗慢性艾滋病毒感染的方法在控制病毒方面是有效的，但这种疾病仍然无效。 是可以治愈的，尽管高效抗逆转录病毒疗法(HAART)取得了成功，但有一个终生的生命，超过36岁 目前有数百万人感染艾滋病毒，现在作为慢性疾病而不是急性疾病进行管理， 但需要终身致力于HAART。HAART中复制能力强的HIV的潜在储备库- 受压抑的个体被认为是治愈的关键障碍，因为长时间的半衰期和持续的 被感染的CD4T细胞储存库。而且，在其潜伏状态下，病毒转录和蛋白质表达的缺乏 在受感染的目标中可以使储蓄者逃脱免疫监视。“先踢后杀”的治愈方法 或者控制HIV包括在HAART期间诱导HIV潜伏期逆转以暴露受感染的细胞，而 产生大量的免疫效应细胞，如细胞毒性T细胞(CTL)，能够消除 这些目标。寻找一种有效的药物手段来暴露和清除无毒的病毒库 方式一直难以捉摸，仍然是这一治愈方法的主要障碍。而树突状细胞(DC)已经 在临床试验中安全地用于在癌症和艾滋病毒环境中驱动CTL反应，我们的一份最近的报告 该小组将DC为基础的HIV疫苗的接种与HAART中残留病毒血症的增加联系在一起。 在分析治疗中断后被抑制的个体，表明基于DC的治疗起作用 作为一名上帝抵抗军。然而，这项临床研究并不是专门针对DC疗法的使用而设计的 作为上帝抵抗军，一些重要的问题仍然存在，包括DC极化和抗原的作用 演示在此效果中发挥的作用，受影响的特定的CD4T细胞储存库，以及潜在的 涉及的机制。在这项建议中，我们将研究两种临床上适用的不同 极化DC类型作为一种体外方法在潜伏感染的CD4T细胞中诱导HIV重新激活 从病毒抑制的HIV-1阳性MACs参与者中获得的细胞。我们将确定最优DC 激活策略促进其LR功能，评估基于DC的LRA对CD4T细胞亚群的影响 方法，探索抗原呈递系统的作用，并执行新的分析来定性评估 用于CTL靶向的HIV-1储存库的DC暴露。来自这些研究的信息最终将用于 开发一种以DC为基础的个性化细胞疗法，旨在促进艾滋病毒的“踢”和“杀”- 作为治愈或控制慢性艾滋病毒-1感染的一项战略。

PROJECT SUMMARY/ABSTRACT While current therapies to treat chronic HIV infection are effective at controlling the virus, the disease is still not curable, and there is a life-long Despite the success of highly active anti-retroviral therapy (HAART), over 36 million people currently live with HIV infection, which is now managed as a chronic rather than acute disease, but requires a lifelong commitment to HAART. The latent reservoir of replication-competent HIV in HAART- suppressed individuals is considered a critical barrier to a cure, due to the long half-life and persistence of the infected CD4+ T cell reservoir. Moreover, in its latent state, the lack of viral transcription and protein expression in the infected targets allows the reservoir to escape immune surveillance. The ‘kick and kill’ approach to curing or controlling HIV involves inducing HIV latency reversal during HAART to expose the infected cells, while creating an arsenal of immune effector cells, such as cytotoxic T cell lymphocytes (CTL), capable of eliminating these targets. Finding an effective pharmacologic means to expose and purge the viral reservoir in a non-toxic manner has been elusive and remains major barrier to this cure approach. While dendritic cells (DC) have been used safely in clinical trials to drive CTL responses in the settings of cancer and HIV, a recent report by our group linked the administration of a DC-based HIV vaccine with increased residual viremia in HAART- suppressed individuals following analytic treatment interruption, suggesting that the DC-based therapeutic acted as an LRA. However, that clinical study was not designed to specifically address the use of the DC therapeutic as an LRA, and a number of important questions remain including the roles that DC polarization and antigen presentation played in this effect, the particular CD4 T cell reservoir that was affected, and the underlying mechanisms involved. In this proposal, we will investigate the use of two clinically applicable differentially polarized DC types as an in vitro approach to induce HIV re-activation in latently infected CD4+ T cells utilizing cells obtained from virally suppressed HIV-1 positive MACS participants. We will determine the optimal DC activation strategy to promote their LR function, assess CD4+ T cell subsets affected by the DC-based LRA approach, explore the role of antigen presentation the system, and perform novel assays to qualitatively assess DC exposure of the HIV-1 reservoir for CTL targeting. Information from these studies will ultimately be used in development of a personalized DC-based cellular therapy designed to facilitate both the ‘kick’ and ‘kill’ of the HIV- 1 reservoir as a strategy towards curing or controlling chronic HIV-1 infection.