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

对树突状细胞进行编程以暴露持久的 HIV-1 潜伏库以实现免疫靶向

• 批准号: 9347740
• 负责人: Robbie B Mailliard
• 金额: $ 23.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347740
• 关键词: Acute Disease; Address; Adjuvant; Affect; Antigen Presentation; Antigens; Autologous; Autologous Dendritic Cells; Biological Assay; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Cytomegalovirus; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Development; Disease; Effectiveness; Effector Cell; Genetic Transcription; HIV; HIV Antigens; HIV Infections; HIV Seropositivity; HIV vaccine; HIV-1; Half-Life; Highly Active Antiretroviral Therapy; Immune; Immune Targeting; Immunity; Immunologic Surveillance; Immunotherapy; In Vitro; Individual; Infection; Inflammatory; Interruption; Life; Link; Lymphocyte; Malignant Neoplasms; Mediating; Methods; Modeling; Participant; Pharmacology; Play; Predisposition; Regulation; Reporting; Residual state; Resources; Rest; Role; Specificity; Staphylococcal Enterotoxin B; System; T-Lymphocyte; Testing; The Multicenter AIDS Cohort Study; Therapeutic; TimeLine; Viral; Viral reservoir; Viremia; Virus; Virus Diseases; base; cell type; clinical application; clinically relevant; design; in vitro Model; in vivo; killings; men; novel; novel strategies; pathogen; polarized cell; pre-clinical; pressure; protein expression; purge; response; sensor; success; therapeutic target; therapy design; vaccine trial

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.

项目总结/摘要 虽然目前治疗慢性艾滋病毒感染的疗法在控制病毒方面是有效的，但这种疾病仍然不是 尽管高效抗逆转录病毒疗法（HAART）取得了成功，但超过36 目前有1000万人感染艾滋病毒，艾滋病毒现在作为慢性病而不是急性病来管理， 但需要终生致力于HAART。HAART中具有复制能力的HIV的潜在储存库- 受抑制的个体被认为是治愈的关键障碍，这是由于受抑制的个体的长半衰期和持久性。 感染的CD 4 + T细胞库。此外，在其潜伏状态下，缺乏病毒转录和蛋白质表达， 使宿主逃脱免疫监视。“踢和杀”的治疗方法 或控制HIV涉及在HAART期间诱导HIV潜伏期逆转以暴露受感染的细胞， 产生免疫效应细胞，如细胞毒性T细胞淋巴细胞（CTL），能够消除 这些目标。找到一种有效的药理学方法，以无毒的方式暴露和清除病毒库， 方式一直难以捉摸，并且仍然是这种治愈方法的主要障碍。树突状细胞（DC） 在临床试验中安全地用于在癌症和HIV背景下驱动CTL应答，我们的研究人员最近的一份报告显示， 研究小组将基于DC的HIV疫苗的施用与HAART中残留病毒血症的增加联系起来， 在分析治疗中断后，受抑制的个体，这表明基于DC的治疗剂 作为一个爱尔兰共和军。然而，该临床研究并不是专门针对DC治疗剂的使用而设计的。 作为LRA，还有一些重要的问题，包括DC极化和抗原 在这种效应中，特定的CD 4 T细胞库受到影响，以及潜在的 涉及的机制。在本提案中，我们将研究两种临床适用的差异 极化DC类型作为体外方法诱导潜伏感染的CD 4 + T细胞中的HIV再活化， 从病毒抑制的HIV-1阳性MACS参与者获得的细胞。我们将确定最佳DC 激活策略，以促进其LR功能，评估基于DC的LRA对CD 4 + T细胞亚群的影响 方法，探索抗原呈递系统的作用，并进行新的测定，以定性评估 用于CTL靶向的HIV-1储库的DC暴露。这些研究的信息最终将用于 开发基于DC的个性化细胞疗法，旨在促进HIV的“踢”和“杀”， 1水库作为治疗或控制慢性HIV-1感染的策略。