Curing HIV Through Allogeneic Hematopoietic Stem Cell Transplantation

项目概要/摘要 艾滋病毒和艾滋病仍然是毁灭性的健康问题，全世界有超过 3000 万人感染艾滋病毒 病毒，每年有数百万人死于艾滋病。联合抗逆转录病毒疗法（cART） 艾滋病的发病率和死亡率下降，但副作用可能很严重，并且药物的出现 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 CD4 T 细胞的储存库。这些细胞的更新速度非常缓慢，导致 尽管有效的 cART 仍会导致储存库持续时间延长，并且停止抗逆转录病毒治疗总是会导致 以至病毒反弹。因此，潜伏病毒库构成了灭菌治疗的主要障碍之一。 艾滋病毒，以及开发新颖的、范式转变的方法可能是成功的长期治疗所必需的。 术语控制。一种这样的新方法是使用同种异体造血干细胞移植（allo- HCT）来治愈艾滋病毒。这种方法的前景在“柏林病人”身上得到了体现，他接受了一种allo- HCT 来自 HIV 抗性 CCR5Δ32 捐赠者，是第一位治愈 HIV 的患者。此外，还有 来自两名“波士顿患者”的令人兴奋的数据，他们接受了来自 CCR5 野生型供体的同种异体 HCT 在连续 cART 治疗期间，以及在治疗中断后数月内能够控制病毒血症的患者。 然而，病毒最终反弹，引发了人们对同种异体 HCT 本身的担忧，而无需用 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 围绕异基因 HCT 治愈 HIV 的机制。这些问题包括 (1) allo-HCT 是否与 艾滋病毒抗性细胞是治愈的必要成分吗？ (2)是否存在移植物抗残留病毒库 （GVRVR）效应，如果是的话，是否可以将其与移植物抗宿主病（GVHD）分开？和（3）可以一个allo- 是否应该制定 HCT 策略，使所有 HIV 患者都能获得治愈性移植？鉴于 由于与异基因 HCT 相关的重大风险，需要临床前模型。然而，直到我们工作之前，没有 根除HIV的allo-HCT临床前模型已经存在，因此，该模型的创建代表了 该领域未满足的关键需求。在本次拨款的 R21 部分期间，我们成功创建了此项目 模型，现在准备使用该模型来回答有关分配的角色的基本问题 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 确定半相合同种异体 HCT 和 GVHD 对 SHIV 储存库的作用。 (2) 我们将确定 是否使用表达 mC46 耐药因子的 HIV 耐药干细胞进行半相合同种异体 HCT 可以根除 SHIV 感染者体内的病毒库。这些目标的顺利完成 将从根本上加深我们对病毒库的细胞和免疫成分的理解， 并将制定新的基于移植的根除艾滋病毒策略。

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.