HIV Infection of Hematopoietic Stem/Progenitor Cells (HSPC) in Bone Marrow

骨髓中造血干细胞/祖细胞 (HSPC) 的 HIV 感染

• 批准号: 8514512
• 负责人: Jerome A. Zack
• 金额: $ 43.43万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-23 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514512
• 关键词: Address; Anatomic Sites; Animals; Antiviral Agents; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell physiology; Cellular Immunity; Clinical; Detection; Development; Effector Cell; Engraftment; Fetal Liver; Generations; Genetic; Genetic Enhancement; Goals; HIV; HIV-1; Hematopoietic; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; Individual; Infection; Inflammatory; Kindling (Neurology); Latent Virus; Marrow; Methods; Mus; Patients; Population; Protocols documentation; Proviruses; Rest; Stem cells; T-Lymphocyte; Testing; Umbilical Cord Blood; Umbilical cord structure; Viral; Virus Diseases; Virus Latency; Virus Replication; Work; antiretroviral therapy; gene therapy; genetic manipulation; human tissue; in vivo; latent infection; mortality; mouse model; progenitor; programs; reconstitution; stem; success; viral RNA

The main objective in human immunodeficiency virus (HIV) therapy is the identification, targeting and elimination of viral reservoirs. While significant progress has been made in the field, the low levels of viral RNA detected in patients under antiretroviral therapy as well as the rebound of viral replication after cessation of such therapy suggest that there are additional HIV reservoirs present. Recent studies have suggested that hematopoietic stem/progenitor cells (HSPC) in the bone marrow can be infected by HIV and harbor latent virus. The goal of the proposed studies is to fully characterize HIV infection in the bone marrow in vivo and to assess the ways to target HIV infected progenitors. As stem cell based gene therapy is considered a potentially new avenue to eradicate HIV, it is essential to fully understand how this new reservoir impacts engraftment of and reconstitution by new stem cells. To address this question we aim to (i) fully characterize HIV infection in HSPC using both humanized mice and human tissues (fetal liver, cord blood) ex vivo, (ii) examine the effect HIV infection has on the bone marrow microenvironment and its ability to support proper lineage development in vivo, and (iii) evaluate gene therapy approaches to impact the viral reservoir, including the development of ways to protect genetically modified antiviral effector cells.

人类免疫缺陷病毒（HIV）治疗的主要目的是识别、靶向和消除病毒宿主。虽然在这一领域取得了重大进展，但在接受抗逆转录病毒治疗的患者中检测到的病毒RNA水平较低，以及停止这种治疗后病毒复制反弹，表明存在其他艾滋病毒储存库。近年来的研究表明，骨髓中的造血干/祖细胞（HSPC）可被HIV感染并携带潜伏病毒。拟议研究的目标是充分表征体内骨髓中的HIV感染，并评估靶向HIV感染祖细胞的方法。由于基于干细胞的基因治疗被认为是根除艾滋病毒的潜在新途径，因此必须充分了解这种新的储库如何影响新干细胞的植入和重建。为了解决这个问题，我们的目标是（i）使用人源化小鼠和人组织充分表征HSPC中的HIV感染（胎肝，脐带血）离体，（ii）检查HIV感染对骨髓微环境的影响及其在体内支持适当谱系发育的能力，和（iii）评估影响病毒储库的基因治疗方法，包括开发保护遗传修饰的抗病毒效应细胞的方法。