Hematopoietic Cell Transplant: Platform for Purging the Latent HIV Reservoir

据报道，造血细胞移植(Hct)已经清除了潜伏的hiv感染者。 一名接受抗艾滋病毒移植物的患者体内的细胞。要使这种方法变得广泛可行，它是 当务之急是，我们必须确定有助于根除该水库的HCT所涉及的因素。 项目1旨在确定Hct的哪些成分对消除潜伏病毒至关重要 水库。项目1的广泛目标是开发一个平台，用于提供艾滋病毒耐药细胞以取代 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水库的单独机制：1)密集 可根除受者淋巴细胞和树突状细胞或抗原提呈细胞的化疗/放射治疗； 2)用未感染HIV的和抗HIV的细胞重建免疫。我们假设两者都是 剂量强度和移植物来源分别有助于消除潜伏感染细胞。以特定的目标 ，我们将在人类受试者中研究1)产生一种 有意义地减少潜伏病毒感染的数量，以及2)移植物来源在消除 潜伏感染的细胞。在特定目标2中，淋巴清除性调节对潜伏的新城疫病毒感染的影响 将在猕猴模型中仔细研究，以便将条件反射的作用与 移植物来源。最后，我们假设，在没有抗艾滋病毒细胞的情况下，潜在的储蓄者最终 将随着时间的推移通过病毒的低水平复制来补充。在具体目标3中，我们将调查来源 通过对病毒序列的系统发育分析，发现负责补充潜伏病毒储存库的艾滋病毒 从血液、脑脊液和肠道中获取，在HCT前后。 项目1的结果将与项目5的结果一起使用，以制定临床交付方案 转基因抗艾滋病毒细胞。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。

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.