Curing HIV Through Allogeneic Hematopoietic Stem Cell Transplantation

 描述：艾滋病毒和艾滋病仍然是毁灭性的健康问题，全世界有3000多万人感染该病毒，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艾滋病毒在含有潜伏感染的静止CD4+T细胞的水库中持续存在。这些细胞翻转非常缓慢，导致尽管CART有效，但储存库持续时间更长，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艾滋病毒绝育治疗的主要障碍之一，而成功的长期控制很可能需要开发新的、改变范式的方法。一种这样的新方法是使用异基因造血干细胞移植(allo-HCT)来治愈艾滋病毒。这一方法的前景在“柏林患者”身上得到了例证，他接受了抗艾滋病毒的CCR5CCR32捐赠者的异基因HCT，他是第一个治愈艾滋病毒的患者。在过去的一年，还有 来自两名波士顿患者的具有挑衅性的数据，他们在连续CART治疗期间接受了CCR5野生型供者的allo-HCT，并在治疗中断后几个月内能够控制病毒血症。然而，病毒最终反弹，这引发了人们的担忧，即allo-HCT本身，如果不与抗HIV的T细胞重组，可能不足以根除病毒。这些配对的发现围绕allo-HCT治愈HIV的机制提出了许多关键问题。这些问题包括(1)带有HIV耐药细胞的异基因HCT是治愈的必要组成部分吗？(2)是否存在移植物抗病毒储存库(GVVR)效应，如果是，这种效应能否与移植物抗宿主病(GVHD)分开？以及(3)能否开发一种异基因HCT策略，使所有HIV+患者都可以进行根治性移植？考虑到与allo-HCT相关的重大风险，临床前模型是必要的。然而，到目前为止，还不存在用于根除艾滋病毒的allo-HCT的临床前模型，因此，该模型的创建仍然是该领域尚未满足的关键需求。在这项应用中，我们将通过完成两个具体目标来满足这一需求：(1)我们将创建用于根除HIV的单倍体相合异基因HCT的猕猴模型；(2)我们将确定使用表达mC46耐药因子的HIV耐药干细胞的单倍体相合HCT是否能够从SHV感染的接受者中根除病毒库。这些目标的成功完成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。

 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.