Targeted Modification of Host and Proviral DNA to Treat Latent HIV Infection

宿主和原病毒 DNA 的靶向修饰治疗潜伏性 HIV 感染

• 批准号: 8691703
• 负责人: KEITH R JEROME
• 金额: $ 406.88万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691703
• 关键词: Address; Antigen-Presenting Cells; Autologous; Biology; Blood; CCR5 gene; CD4 Positive T Lymphocytes; Cell Transplants; Cells; Cerebrospinal Fluid; Chemokine (C-C Motif) Receptor 5; Chronic; Cities; Clinical Protocols; Collaborations; Complementary DNA; DNA; Dendrimers; Dose; Engineering; Fingers; Genetic; Goals; HIV; HIV Infections; HIV Receptors; Health; Hematopoietic; Hematopoietic System; Homing; Human; Immunity; Individual; Infection; Institution; Intestines; Lymphocyte; Macaca; Messenger RNA; Modeling; Modification; Mutate; Pathway interactions; Patients; Phylogenetic Analysis; Positioning Attribute; Primates; Proviruses; Radiation therapy; Regimen; Relative (related person); Reporting; Research; Research Infrastructure; Research Institute; Research Personnel; Resistance; Resistance to infection; Rest; Role; Scientist; Sequence Analysis; Site-Directed Mutagenesis; Source; Stem cells; Technology; Time; Translational Research; Transplant Recipients; Transplantation; Viral; Virus Diseases; Virus Replication; Work; aptamer; conditioning; design; endonuclease; hematopoietic cell transplantation; human subject; nonhuman primate; novel strategies; nuclease; programs; purge; reconstitution; research study; simian human immunodeficiency virus; zinc finger nuclease

DESCRIPTION (provided by applicant): A major obstacle to long-term control and cure of HIV has been the persistence of HIV in reservoirs that contain latently infected, resting, and productively infected CD4+ T cells. The recent cure of a patient with HIV by hematopoietic cell transplantation (HCT) with HIV-resistant cells has demonstrated the enormous potential of this strategy. Unfortunately, HIV-resistant donors are extremely rare, severely limiting this approach. Here we propose a multi-investigator program to study the biology of the HIV reservoir in patients and nonhuman primates, and to develop novel strategies to repopulate the hematopoietic system with HIV-resistant cells. We have assembled a team consisting of leaders in the fields of HIV, genetic modification, translational research, and transplantation. Specifically, we will combine autologous HCT with genetic modification approaches, allowing us to disrupt the CCR5 receptor in autologous stem cells, and also destroy the integrated HIV provirus contained within those cells. We propose 5 highly integrated projects in pursuit of our overall goal, and 5 cores for their support. Project 1, Hematopoietic Cell Transplant: Platform for Purging the Latent HIV Reservoir (Ann Woolfrey, FHCRC), will seek to clarify the relative contributions of the preparative regimen and the donor graft required for purging the latent HIV reservoir. Project 2, ZFN-Modified Stem Cells for HIV Eradication (Philip Gregory, Sangamo Biosciences), will seek to endow the transplant recipient's own cells with stable resistance to infection, via zinc finger nuclease disruption of the CCR5 locus. Project 3, CCR5 Targeting to Control HIV/SHIV in Nonhuman Primates (Hans-Peter Kiem, FHCRC), will use a non-human primate model of HIV/SHIV infection to determine whether genetic modification of the CCR5 locus and HCT can provide long-term control of HIV. Project 4, Targeted Disruption of Integrated SHIV by Engineered Homing Endonucleases, (Keith Jerome, FHCRC), will seek to directly address the problem of viral persistence, by designing highly specific homing endonucleases that can recognize and mutate integrated SHIV provirus in infected macaque hematopoietic cells. Project 5, Aptamer and Dendrimer Delivery of Zn Finger Nuclease and Homing Endonuclease mRNA and cDNA (John Rossi, Beckman Research Institute of the City of Hope), will develop and optimize delivery strategies by which ZFNs and HEs can be delivered to their target cells. Given our leading roles in Transplantation and HIV research, we believe we are uniquely positioned to move these concepts from a highly relevant nonhuman primate HIV/SHIV model toward a cure for HIV-infected patients.

描述（由申请人提供）：长期控制和治愈HIV的一个主要障碍是HIV在含有潜伏感染、静息和生产性感染的CD 4 + T细胞的储库中的持续存在。最近通过使用抗HIV细胞的造血细胞移植（HCT）治愈了一名HIV患者，证明了这种策略的巨大潜力。不幸的是，抗艾滋病毒的捐赠者非常罕见，严重限制了这种方法。在这里，我们提出了一个多研究者计划，研究患者和非人灵长类动物中HIV储库的生物学，并开发新的策略，用HIV抗性细胞重新填充造血系统。我们已经组建了一个由艾滋病毒，遗传修饰，转化研究和移植领域的领导者组成的团队。具体来说，我们将联合收割机自体HCT与遗传修饰方法相结合，使我们能够破坏自体干细胞中的CCR 5受体，并破坏这些细胞中包含的整合的HIV前病毒。我们提出了5个高度集成的项目来追求我们的总体目标，并提出了5个核心来支持它们。项目1，造血细胞移植：清除潜伏HIV库的平台（Ann Woolfrey，FHCRC），将寻求澄清清除潜伏HIV库所需的准备方案和供体移植物的相对贡献。项目2，ZFN修饰的干细胞用于HIV根除（Philip Gregory，Sangamo Biosciences），将寻求通过锌指核酸酶破坏CCR 5位点，赋予移植受体自身的细胞稳定的抗感染能力。项目3，CCR 5靶向控制非人灵长类动物中的HIV/SHIV（Hans-Peter Kiem，FHCRC），将使用HIV/SHIV感染的非人灵长类动物模型来确定CCR 5基因座和HCT的遗传修饰是否可以长期控制HIV。项目4，通过工程化归巢核酸内切酶靶向破坏整合的SHIV，（基思杰罗姆，FHCRC），将寻求通过设计高度特异性的归巢核酸内切酶来直接解决病毒持续存在的问题，该核酸内切酶可以识别并突变感染的猕猴造血细胞中的整合的SHIV前病毒。项目5，锌指核酸酶和归巢核酸内切酶mRNA和cDNA的适体和树枝状聚合物递送（John Rossi，Beckman Research Institute of the City of Hope），将开发和优化递送策略，通过该策略可以将ZFN和HE递送到它们的靶细胞。鉴于我们在移植和HIV研究中的领导地位，我们相信我们具有独特的优势，可以将这些概念从高度相关的非人灵长类HIV/SHIV模型转向治愈HIV感染患者。