Role of co-receptor modified cells in HIV infection

该项目1的中心假设是CCR 5缺陷的（C 04-）-T细胞在C 04-）-T细胞中起主要作用。 为柏林病人的成功治疗做出了贡献。我们的方法是基于我们的专业知识， 基于细胞的HIV感染治疗以及来自自体CD 4输注的第一个人体数据 锌指核酸酶（ZFN）使CCRs缺陷的细胞，whk：h结合，切割并灭活ccrS 基因该试验的I期数据显示了极好的安全性特征以及有效的、长期的 CCRS修饰的细胞的植入和扩增。此外，虽然不是这次审判的直接目标， 在宾夕法尼亚大学完成12周治疗的6名受试者中观察到了有趣的抗病毒效果 中断，在本项目中，我们将确定患者是否接受单剂量环磷酰胺预处理 通常用于自身免疫性疾病，并促进免疫治疗， 用RS特异性ZFN处理的自体T细胞，并且因此，在不存在HIV-1 T的情况下控制HIV。 提出了三个具体目标：（1）完成必要的临床前试验，以支持 mRNA ZFN修饰的CD 4 T细胞的制备;（2）进行概念验证临床试验以确定ZFN修饰的CD 4 T细胞的表达。 在短暂性淋巴细胞减少症的情况下输注R5缺陷型CD 4细胞的安全性， 剂量的环磷酰胺和（3）评价宿主对R5修饰的T细胞的应答和病毒学应答 输液我们推测，在环磷酰胺治疗的小鼠中， 与此相关，在结构化的治疗中断期间，将发现抗病毒作用。 在没有HAART的情况下治愈或控制艾滋病毒一直是一个难以捉摸的目标，但最终可能会实现。 实现了我们的项目的结果，与一个经验丰富的团队在Sangamo和宾夕法尼亚州进行，将 为将来的研究方案提供了关键信息，以进一步研究导致Beriin治愈的因素 耐心，并提供基本的见解，以underiying机制。

The central hypothesis of this Project 1 is that CCR5-deficient, C04-)- T-cells played a major role in contributing to the successful outcome of the Berlin patient. Our approach is tiased on our expertise with cell'based therapies for HIV infection as well as the first in-human data from Infusions of autologous CD4 cells rendered CCRS-deficient by zinc finger nucleases (ZFNs), whk:h bind to, cleave and Inactivate the ccrS gene. Phase-I data from this trial demonstrated an excellent safety profile as well as efficient, long-temn engraftment and expansion of the CCRS-modified cells. Furthermore, while not a direct goal of this trial, intriguing antiviral effects have been observed in 6 subjects at Penn who completed a 12 week treatment interruption, in this project we will detennine if patient conditioning with a single dose of cyclophosphamide that is used routinely in autoimmune disorders and to promote immunotherapy can enhance engraftment of autologous T-cells treated with RS-spedfic ZFNs, and as a result, control HIV In the absence of H/\/^T. Three specific aims are proposed: (1) Complete the pre-clinical testing necessary to support the manufacturing of mRNA ZFN modified CD4 T cells; (2) Conduct a proof of concept clinical trial to detennine the safety of R5 deficient CD4 cells infused in the setting of transient lymphopenia, induced with a single dose of cyclophosphamide and (3) Evaluate the host and virotogical response to R5-modified T ceil infusions. We hypothesize that the level of engraftment will increase in the cyclophosphamide-treated patients, and related to this, ttiat antiviral effects will be uncovered during a structured treatment interruption. Curing or controlling HIV in the absence of HAART has been an elusive goal, but one that may finally be realized. The results of our project, conducted with an experienced team in place at Sangamo and Penn will provide critical information for future protocols to further dtesect the factors that led to cure of the Beriin patient and provide basic insights into underiying mechanisms.