A nonhuman primate model of stem cell transplantation to understand determinants of post-transplant SIV clearance

项目摘要 由于目前艾滋病毒感染者人数达到历史上最多的水平，阻止艾滋病毒的流行仍然是当务之急。 联合抗逆转录病毒疗法（ART）限制病毒复制，但不能治愈。因此，迫切需要 通过消除病毒库来设计功能性治疗方法。蒂莫西·布朗又名柏林病人和亚当 卡斯蒂列霍，又名伦敦病人，在白血病相关的，MHC匹配的，同种异体移植后， 造血干细胞移植（HSCT）从CCR5缺陷的供体。使用我们的同种异体HSCT模型 在猕猴（MCM）中，我们已经证明同种异体免疫应答可以 有效地清除潜在的水库，但最终是不够的，由于感染的易感性。这突出表明 CCR5缺陷的供体需要在HSCT的背景下完全根除HIV。在我们的 我们先前的研究已经证明，CCR5特异性抗体Leronlimab可以模拟CCR5缺陷型 供体通过占据所有可用的CCR5分子。我们现在建议在以下情况下使用Leronlimab： 同种异体造血干细胞移植，以明确证明CCR5缺陷实现HIV治愈的机制。在 具体目的1，我们将测量Leronlimab给药的效果并确定其在治疗期间的机制。 在接受同种异体HSCT的SHIV感染、ART抑制的MCM中的围移植期。在具体目标2中， 我们将测量是否在移植围手术期在接受治疗的HIV+患者中给予Leronlimab， 用于癌症治疗的同种异体HSCT可以复制CCR5缺陷供体并介导HIV治愈。这项工作 这将扩大我们对异基因造血干细胞移植治疗HIV机制的认识，并建立一个 新的艾滋病治疗方法。

PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (ART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure via elimination of the viral reservoir. Timothy Brown, aka the Berlin Patient, and Adam Castillejo, aka the London patient, were cured of HIV following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5-deficient donor. Using our allogeneic HSCT model in Mauritian cynomolgus macaque (MCM), we have demonstrated that the allogeneic immune response can potently purge the latent reservoir, but is ultimately insufficient due to susceptibility to infection. This underscores the need for CCR5 deficient donors to fully eradicate HIV in the setting of HSCT. During the course of our previous studies we have demonstrated that the CCR5-specific antibody Leronlimab can mimic a CCR5 deficient donor by occupying all available CCR5 molecules. We are now proposing to utilize Leronlimab in the setting of allogeneic HSCT to definitely demonstrate the mechanism by which CCR5 deficiency achieves HIV cure. In specific aim 1, we will measure the effect and determine the mechanism of Leronlimab administration during the peri-transplant period in SHIV-infected, ART-suppressed MCM undergoing allogeneic HSCT. In specific aim 2, we will measure if Leronlimab administered during the peri-transplant period in an HIV+ patient undergoing allogenic HSCT for cancer treatment can replicate a CCR5-deficient donor and mediate an HIV cure. This work would expand our knowledge of the mechanism of HIV cure in the setting of allogeneic HSCT and establish a new therapeutic treatment for HIV cure.