Curing HIV Through Allogeneic Hematopoietic Stem Cell Transplantation

项目总结/摘要 艾滋病毒和艾滋病仍然是破坏性的健康问题，全世界有3000多万人感染艾滋病毒和艾滋病。 艾滋病病毒，每年有数百万人死于艾滋病。联合抗逆转录病毒治疗（cART） 降低艾滋病的发病率和死亡率，但副作用可能很严重， 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非洲的持续存在。 含有潜伏感染的静息CD 4 + T细胞的储库。这些细胞翻转非常缓慢，导致 尽管cART有效，但储库持续时间延长，停止抗逆转录病毒治疗总是导致 病毒反弹因此，潜伏的病毒库构成了对感染者进行灭菌治疗的主要障碍之一。 艾滋病毒，以及新的，范式转变的方法的发展可能需要成功的长期- 术语控制。一种这样的新方法是使用异基因造血干细胞移植（allo- HCT）来治愈HIV。这种方法的前景在“柏林病人”身上得到了体现， 来自HIV耐药CCR 5 Δ32供体的HCT，是第一个治愈HIV的患者。此外，还有 来自两名接受来自CCR 5野生型供体的allo-HCT的“波士顿患者”的数据引起了争议 在连续的cART治疗期间，并且能够在治疗中断后控制病毒血症数月。 然而，病毒最终反弹，引起了人们的担忧，即allo-HCT本身，没有与HIV重组， 抵抗性T细胞，可能不足以根除病毒。这些成对的发现提出了许多关键问题 allo-HCT治疗HIV的机制。这些问题包括：（1）allo-HCT是否具有 抗艾滋病毒细胞是治疗的必要组成部分？(2)是否存在移植物抗残留病毒库 （GVRVR）的影响，如果是这样，这可以从移植物抗宿主病（GVHD）分开？（3）一个allo- 制定HCT策略，使所有HIV+患者都能获得治愈性移植？鉴于 与allo-HCT相关的显著风险，需要临床前模型。然而，直到我们的工作，没有 存在allo-HCT用于HIV根除的临床前模型，因此，该模型的创建代表了 这是外地一个尚未满足的关键需求。在此补助金的R21部分，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允许的角色的基本问题， HCT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做到这一点：（1）我们将 确定单倍体相合的allo-HCT和GVHD对SHIV储库的作用。(2)我们将确定 是否使用表达mC 46抗性因子的HIV抗性干细胞的单倍体相合异基因HCT 可以从感染HIV的接受者身上根除病毒库。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成分的理解， 并将建立新的基于移植的艾滋病毒根除战略。

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.