Curing HIV Through Allogeneic Hematopoietic Stem Cell Transplantation

 产品说明：艾滋病毒和艾滋病仍然是破坏性的健康问题，全世界有3 000多万人感染这种病毒，每年有数百万人死于艾滋病。联合抗逆转录病毒疗法（cART）大大降低了艾滋病的发病率和死亡率，但副作用可能很严重，耐药性的出现是一个持续的挑战。治愈这种病毒的一个主要障碍是HIV在含有潜伏感染的静息CD 4 + T细胞的储库中的持续存在。这些细胞的转化非常缓慢，导致尽管cART有效，但储库持续时间延长，并且抗逆转录病毒治疗的停止总是导致病毒反弹。因此，潜伏的病毒库构成了对HIV进行灭菌治疗的主要障碍之一，并且成功的长期控制可能需要开发新的范式转变方法。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“柏林患者”中得到了例证，该患者接受了来自HIV耐药CCR 5 β 32供体的allo-HCT，并且是第一个治愈HIV的患者。去年， 来自两名“波士顿患者”的激动性数据，他们在连续cART治疗期间接受来自CCR 5-野生型供体的allo-HCT，并且他们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，即在没有与HIV抗性T细胞重建的情况下，allo-HCT本身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，围绕allo-HCT可以治愈HIV的机制。这些问题包括（1）具有HIV抗性细胞的allo-HCT是治愈的必要组成部分吗？(2)是否存在移植物抗病毒储库（GVVR）效应？如果存在，是否可以将其与移植物抗宿主病（GVHD）分开？和（3）是否可以开发一种allo-HCT策略，使所有HIV+患者都能获得治愈性移植？鉴于allo-HCT相关的重大风险，需要临床前模型。然而，到目前为止，还不存在用于HIV根除的allo-HCT的临床前模型，因此，该模型的创建仍然是该领域未满足的关键需求。在本申请中，我们将通过完成两个具体目标来解决这一需求：（1）我们将创建用于HIV根除的单倍相合allo-HCT的猕猴（macaca nemestrina）（猪尾猕猴）模型;以及（2）我们将确定使用表达mC 46抗性因子的HIV抗性干细胞的单倍相合HCT是否可以从HIV感染的受体中根除病毒储库。这些目标的成功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策略。

 DESCRIPTION: 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 CCR5 32 donor, and is the first patient cured of HIV. In the last year, there was also 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-viral-reservoir (GVVR) 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, to date, no preclinical model of allo-HCT for HIV eradication exists, and therefore, the creation of this model remains a critical unmet need in the field. In this application, we will address this need through the completion of two Specific Aims: (1) We will create a macaca nemestrina (pig-tailed macaque) model of haploidentical allo-HCT for HIV eradication; and (2) We will determine whether haploidentical 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.