Curing HIV Through Allogeneic Hematopoietic Stem Cell Transplantation

项目摘要/摘要 艾滋病毒和艾滋病继续是毁灭性的健康问题，全世界有3000多万人感染了艾滋病毒。 这种病毒，以及每年数百万人死于艾滋病。联合抗逆转录病毒疗法(CART)在很大程度上 降低了艾滋病的发病率和死亡率，但副作用可能很严重，药物的出现 抵抗是一个持续的挑战。治愈这种病毒的一个主要障碍是艾滋病毒在 含有潜伏感染的静息CD4T细胞的蓄水池。这些细胞翻转得非常慢，导致 尽管CART有效，但持续时间延长，以及停止抗逆转录病毒治疗总是会导致 病毒反弹。因此，潜伏的病毒库构成了灭菌治疗的主要障碍之一 艾滋病毒，以及开发新的、范式转换的方法可能是成功的长期- 学期控制。一种这样的新方法是使用异基因造血干细胞移植(异体-干细胞移植)。 HCT)来治愈艾滋病毒。这种方法的前景在一位收到异名-《柏林病人》的病人身上得到了体现。 Hct来自抗艾滋病毒的CCR5CCR32捐赠者，是第一个治愈艾滋病毒的患者。此外，还有 来自两名波士顿患者的具有挑衅性的数据，他们接受了CCR5野生型捐赠者的allo-HCT 在连续CART治疗期间，以及在治疗中断后几个月内能够控制病毒血症的患者。 然而，病毒最终反弹，引发了人们的担忧，即allo-hct本身，没有与HIV重组- 抗性T细胞，可能不足以根除病毒。这些配对的发现提出了许多关键问题 围绕allo-hct治愈HIV的机制。这些问题包括：(1)异体HCT与 抗HIV细胞是治愈方法的必要组成部分吗？(2)是否存在移植物抗残留病毒库 (GVRVR)效应，如果是这样，这能否与移植物抗宿主病(GVHD)分开？以及(3)同种异体可以- 制定HCT战略，使所有艾滋病毒患者都可以进行根治性移植？给定 与allo-HCT相关的重大风险，需要一个临床前模型。然而，在我们的工作之前，没有 存在用于根除HIV的allo-HCT的临床前模型，因此，该模型的创建代表了 这一领域尚未得到满足的关键需求。在此赠款的R21部分期间，我们成功地创建了 模型，现在准备使用这个模型来回答关于All-Alo- 红细胞压积可以在根除HIV方面发挥作用。我们将通过以下两个具体目标来实现这一点：(一)我们将 确定单倍体相合的allo-Hct和GVHD在SHIV储备库中的作用。(2)我们会决定 是否使用表达mC46耐药因子的HIV耐药干细胞进行半相合异基因HCT 可以根除受SHV感染的接受者体内的病毒库。这些目标的圆满实现 将从根本上加深我们对病毒库的细胞和免疫学成分的理解， 并将建立以移植为基础的根除艾滋病毒的新战略。

PROJECT SUMMARY/ABSTRACT HIV and AIDS continue to be devastating health problems, with over 30 million people worldwide infected with the virus, and millions of deaths each year from AIDS. Combination antiretroviral therapy (cART) has greatly decreased morbidity and mortality from AIDS, but the side effects can be severe and the emergence of drug resistance an ongoing challenge. A major obstacle to the cure of this virus has been HIV persistence in reservoirs that contain latently infected resting CD4+ T cells. These cells turn over very slowly, leading to prolonged reservoir persistence despite effective cART, and cessation of antiretroviral therapy invariably leads to virus rebound. The latent viral reservoir thus constitutes one of the major barriers to a sterilizing cure for HIV, and the development of novel, paradigm-shifting approaches will likely be required for successful long- term control. One such novel approach is the use of allogeneic hematopoietic stem cell transplant (allo- HCT) to cure HIV. The promise of this approach is exemplified in the `Berlin patient' who received an allo- HCT from an HIV-resistant CCR5Δ32 donor, and is the first patient cured of HIV. In addition, there has also emerged provocative data from the two `Boston Patients', who received allo-HCT from CCR5-wildtype donors during continuous cART treatment, and who were able to control viremia for months after therapy interruption. However, virus eventually rebounded, raising concerns that allo-HCT itself, without reconstitution with HIV- resistant T-cells, may be insufficient to eradicate virus. These paired findings raise many critical questions surrounding the mechanisms by which allo-HCT could cure HIV. These questions include (1) Is allo-HCT with HIV-resistant cells a necessary component to the cure? (2) Is there a graft-versus-residual-viral-reservoir (GVRVR) effect, and if so, can this be separated from graft-versus-host disease (GVHD)? and (3) Can an allo- HCT strategy be developed that would make curative transplant available to all HIV+ patients? Given the significant risks associated with allo-HCT, a preclinical model is required. However, until our work, no preclinical model of allo-HCT for HIV eradication existed, and therefore, the creation of this model represented a critical unmet need in the field. During the R21 portion of this grant, we have successfully created this model, and are now poised to use this model to answer fundamental questions about the role that allo- HCT can play in eradication of HIV. We will do this through the following two Specific Aims: (1) We will determine the role of haploidentical allo-HCT and GVHD on the SHIV reservoir. (2) We will determine whether haploidentical allo-HCT using HIV-resistant stem cells expressing the mC46 resistance factor can eradicate the viral reservoir from SHIV-infected recipients. The successful completion of these aims will fundamentally deepen our understanding of the cellular and immunologic components of the viral reservoir, and will establish novel transplant–based strategies for HIV eradication.