Role of co-receptor modified cells in HIV infection

这个项目1的中心假设是CCR5缺陷的，C04-)-T细胞在 为柏林患者的成功结局做出了贡献。我们的方法基于我们在以下方面的专业知识 HIV感染的基于细胞的治疗以及第一批输入自体CD_4的人体数据 锌指核酸酶(ZFN)导致CCRs缺陷的细胞，WHK：H与CCRs结合、裂解和失活 吉恩。这项试验的I期数据显示了极好的安全性以及高效、长时间的TEMN CCRs修饰细胞的植入和扩增。此外，虽然这不是这次试验的直接目标， 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耐人寻味的抗病毒效果。 中断，在这个项目中，我们将确定9名患者是否接受了单剂量环磷酰胺的调节 这是自身免疫性疾病的常规使用，并促进免疫治疗可以增强植入 用RS特异的ZFN处理自体T细胞，结果是在没有H//^T的情况下控制了HIV。 提出了三个具体目标：(1)完成必要的临床前测试，以支持 制造mRNA ZFN修饰的CD4T细胞；(2)进行概念验证临床试验以确定 R5缺陷的CD4细胞输注在单次注射诱导的短暂性淋巴细胞减少症中的安全性 环磷酰胺剂量和(3)评价R5修饰T细胞的宿主和病毒学应答 输液。我们推测，在环磷酰胺治疗后，植入水平将增加。 与此相关，TTAT的抗病毒效果将在结构化治疗中断期间被发现。 在没有HAART的情况下治愈或控制HIV一直是一个难以实现的目标，但最终可能是 意识到了。我们在桑加莫和宾夕法尼亚的经验丰富的团队进行的项目的结果将 为未来的方案提供关键信息，以进一步检测导致小儿麻痹症治愈的因素 并提供对潜在机制的基本见解。

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.