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: 8202333
• 负责人: ANN E WOOLFREY
• 金额: $ 20.65万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8202333
• 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 HIV 感染者的储存库 一名接受了抗艾滋病毒移植物的患者体内的细胞。为了使这种方法变得广泛可行， 我们必须确定 HCT 中涉及的有助于根除储存库的因素。 项目 1 旨在确定 HCT 的哪些成分对于消除潜伏病毒至关重要 水库。项目 1 的总体目标是开发一个平台，用于输送抗 HIV 细胞以替代 潜伏感染的细胞。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存库的单独机制：1）强化 化疗/放疗可根除受体淋巴细胞和树突状细胞或抗原呈递细胞； 2）用未感染艾滋病毒和抗艾滋病毒的细胞重建免疫力。我们假设两者 剂量强度和移植物来源分别有助于消除潜伏感染的细胞。特定目标 1，我们将在人类受试者中研究 1) 产生的调节剂量强度 有意义地减少潜伏病毒感染的数量，以及 2) 移植源在消除病毒感染方面的作用 潜伏感染的细胞。在具体目标 2 中，淋巴清除调理对潜在 SHIV 感染的影响 将在猕猴模型中进行仔细研究，以便将调节作用与 嫁接来源。最后，我们假设，在没有 HIV 抗性细胞的情况下，潜在的病毒库最终 随着时间的推移，病毒的低水平复制将得到补充。在具体目标 3 中，我们将调查来源 通过病毒序列的系统发育分析，确定负责补充潜在储存库的 HIV 在 HCT 之前和之后从血液、脑脊液和肠道中获取。 项目 1 的结果将与项目 5 的结果一起用于制定临床交付方案 基因改造的 HIV 抗性细胞。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 Core C 进行。