Hematopoietic Cell Transplant: Platform for Purging the Latent HIV Reservoir

造血细胞移植：清除潜伏艾滋病毒库的平台

• 批准号: 8376024
• 负责人: ANN E WOOLFREY
• 金额: $ 27.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8376024
• 关键词: Allogenic; Anatomic Sites; Anti-Retroviral Agents; Antigen-Presenting Cells; Autologous; Biology; Blood; CCR5 gene; CD4 Positive T Lymphocytes; Cell Transplants; Cells; Cerebrospinal Fluid; Chimerism; Clinical; Clinical Protocols; DNA; Data; Disease; Dose; Engraftment; Gene-Modified; Goals; Gut associated lymphoid tissue; Hematologic Neoplasms; Hematopoietic; Highly Active Antiretroviral Therapy; Human; Immune; Immunity; Immunologics; Infection; Institution; Intestines; Knowledge; Lymphocyte; Lymphoma; Macaca; Measurable; Measurement; Methods; Modeling; Molecular; Patients; Phylogenetic Analysis; Pre-Clinical Model; Primates; Radiation therapy; Reagent; Regimen; Relative (related person); Reporting; Research Personnel; Resistance; Risk; Role; Sampling; Satellite Viruses; Sequence Analysis; Site-Directed Mutagenesis; Source; Techniques; Time; Transplantation; Transplantation Immunology; Viral; Virus; Virus Diseases; Virus Replication; Whole-Body Irradiation; conditioning; gene therapy; genetic analysis; graft vs host disease; human MCAM protein; human subject; leukemia; novel; prevent; purge; reconstitution; research study; simian human immunodeficiency virus

Hematopoietic cell transplant (HCT) has been reported to have purged the reservoir of latently HIV-infected cells in one patient who received an HIV-resistant graft. For this approach to become broadly feasible, it is imperative that we determine the factors involved in HCT that contribute to eradication of the reservoir. Project 1 aims to determine what components of HCT are critical for elimination of the latent viral reservoir. The broad aim of Project 1 is to develop a platform for delivery of HIV-resistant cells to replace latently infected cells. In order to accomplish this broad goal, it is imperative that we determine the role of the separate mechanisms that may contribute to long-term elimination of the reservoir: 1) intensive chemo/radiotherapy which may eradicate recipient lymphocytes and dendritic or antigen presenting cells; and 2) reconstitution of immunity with HIV-uninfected and HIV-resistant cells. We hypothesize that both dose-intensity and graft source contribute separately to elimination of latently infected cells. In Specific Aim 1, we will investigate in human subjects both 1) the dose-intensity of conditioning that produces a meaningful reduction in the quantity of latent viral infection, and 2) the role of the graft source in eliminating latently infected cells. In Specific Aim 2, the effect of a lymphoablative conditioning on latently SHIV infection will be studied carefully in a macaque model, so as to separate the role of conditioning from the role of the graft source. Finally, we hypothesize that, in the absence of HIV-resistant cells, the latent reservoir ultimately will be replenished over time by low level replication of virus. In Specific Aim 3, we will investigate the source of HIV responsible for replenishing the latent reservoir, by a phylogenetic analysis of viral sequences obtained from blood, cerebral spinal fluid, and the intestinal tract, before and after HCT. Result from Project 1 will be used together with that from Project 5 to develop a clinical protocol for delivery of genetically modified HIV resistant cells. Project 1 will rely heavily on Core A and Core B, for support of the primate experiments. The phylogenetic sequencing and analysis will be performed by Core C.

据报道，造血细胞移植（HCT）已清除了潜在的HIV感染的储层 一名接受抗HIV的移植物的患者的细胞。为了使这种方法变得广泛可行，这是 我们必须确定HCT中涉及的因素，这些因素有助于根除储层。 项目1旨在确定哪些HCT的组成部分对于消除潜在病毒至关重要 水库。项目1的广泛目的是开发一个抗艾滋病毒细胞的平台以替换 潜在感染的细胞。为了实现这一广泛目标，我们必须确定 可能有助于长期消除储层的单独机制：1）密集型 化学/放射疗法可能会消除受体淋巴细胞以及树突状或抗原呈递细胞的化学疗法； 2）用艾滋病毒未感染和抗HIV的细胞重构免疫。我们假设这两个 剂量强度和移植物源分别有助于消除潜在感染的细胞。在特定目标中 1，我们将在人类受试者中调查1）产生A的调节剂量强度 有意义的减少潜在病毒感染的数量，以及2）移植物来消除移植物的作用 潜在感染的细胞。在特定的目标2中，淋巴结条件对潜在的SHIV感染的影响 将在猕猴模型中仔细研究，以将调节的作用与 移植物来源。最后，我们假设在没有抗HIV的细胞的情况下，潜在储层最终 随着时间的流逝，将通过病毒的低水平复制来补充。在特定目标3中，我们将调查来源 由病毒序列的系统发育分析，负责补充潜在储层的艾滋病毒 HCT前后，从血液，脑脊髓液和肠道获得。 项目1的结果将与项目5一起使用，以制定交付临床方案 基因抗HIV的抗HIV细胞。项目1将严重依赖核心A和核心B，以支持 灵长类动物实验。系统发育测序和分析将由CoreC进行。