Graft versus host immunity in SIV clearance following stem cell transplantation.

描述(申请人提供)：由于目前有3400万艾滋病毒携带者，遏制艾滋病毒流行仍是当务之急。联合抗逆转录病毒疗法(CART)可以限制病毒复制，但不能治愈。因此，迫切需要设计一种消除病毒库的功能性治疗方法。目前有3名HIV患者在接受白血病相关、MHC相合的异基因造血干细胞移植(HSCT)后，在没有CART的情况下仍未感染HIV。这种功能性治愈的机制尚不清楚，但可能取决于移植受者的移植物抗宿主免疫。非人灵长类动物是HIV感染的最佳模型，但由于非人灵长类动物MHC的复杂性，大多数研究集中在自体或MHC不匹配的同种异体造血干细胞移植上。因此，还没有研究直接评估移植物抗宿主免疫在MHC相合的异基因造血干细胞移植后清除HIV储存库中的作用。我们打算使用一种新的毛里求斯食蟹猴(MCM)模型来确定移植物抗宿主免疫对HSCT后HIV清除的贡献。大约500年前，由于最近的一个瓶颈，MCM极大地简化了遗传学。因此，我们能够很容易地识别MHC完全匹配的动物，这种情况类似于人类HSCT中最常见的MHC匹配。在具体目标1中，我们将在SIV感染的MCM中建立一种安全有效的非清扫方案。在特定的目标2中，我们将进行MHC相合的HSCT，测量移植物抗宿主免疫，并将其与SIV在血浆和组织中的反弹相关联。总体而言，这项研究将建立 在非人类灵长类动物中进行MHC相合的异基因HSCT的新模型，并使用该模型评估移植物抗宿主免疫在HSCT后HIV清除中的作用。

DESCRIPTION (provided by applicant): With 34 million people currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (cART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure va elimination of the viral reservoir. There are now 3 HIV patients who remain HIV free in the absence of cART following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT). The mechanisms underlying this functional cure are not known, but may depend on graft-versus-host immunity in the transplant recipients. Non-human primates are the best model of HIV infection, but the majority of studies focus on autologous or MHC-mismatched allogeneic HSCT due to the complexity of non-human primate MHC. Thus, no studies have directly assessed the role of graft-versus-host immunity in the clearance of the HIV reservoir following MHC-matched, allogeneic HSCT. We intend to define the contribution of graft-versus-host immunity to HIV clearance following HSCT using a novel, Mauritian Cynomolgus macaque (MCM) model. MCM have extremely simplified genetics due to a recent bottleneck approximately 500 years ago. Therefore, we are able to readily identify fully MHC-matched animals, a situation akin to the MHC-matching most often performed in human HSCT. In specific aim 1, we will establish a safe and effective nonmyeoablative regimen in SIV-infected MCMs. In specific aim 2, we will perform MHC-matched HSCT, measure graft-versus host immunity, and correlate it to SIV rebound in the plasma and tissues. Overall, this study will build a new model of MHC-matched, allogeneic HSCT in non-human primates and use this model to assess the role of graft-versus-host immunity in HIV clearance following HSCT.