Investigating graft-versus-host clearance of HIV-infected cells in vivo

研究体内 HIV 感染细胞的移植物抗宿主清除

基本信息

批准号：
9053451
负责人：
Perry Meng-che Tsai
金额：
$ 4.04万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053451
关键词：
Address Adherence Allogeneic Bone Marrow Transplantation Allogenic Animal Model B-Lymphocytes Berlin Bone Marrow Bone Marrow Transplantation Boston CCR5 gene CD4 Positive T Lymphocytes Case Study Cells Cessation of life Chronic Clear Cell DNA Dendritic Cells Development Donor Lymphocyte Infusion Engraftment Environment Ethics Foundations Funding Future Goals HIV Health Health Care Costs Hematopoietic Human Immune Immunologic Deficiency Syndromes Immunology Incidence Infection Infectious Disease Immunology Infusion procedures Interphase Cell Interruption Kinetics Laboratories Leukemic Cell Life Liver Lymphocyte Malignant Neoplasms Mentors Modeling Morbidity - disease rate Mus Mutation Neoplasms Osteoporosis Outcome Pathogenesis Patients Physicians Play Relapse Reporting Research Resistance Rest Role Scientist Solid Source T-Cell Depletion T-Lymphocyte Testing Thymus Gland Time Toxic effect Training Translational Research Transplantation Transplantation Immunology Update Viral Viral Load result Viral reservoir Viremia Virus Virus Diseases Work anticancer research antiretroviral therapy cardiovascular disorder risk career cost gene therapy human subject humanized mouse in vivo innovation leukemia macrophage monocyte mortality mouse model peripheral blood pre-doctoral prevent reconstitution research study viral DNA viral RNA

项目摘要

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV) remains a major source of morbidity, mortality, and healthcare costs worldwide. In 2011 alone, 34 million people were living with HIV, with 2.5 million new infections and 1.7 million deaths. Although antiretroviral therapy (ART) can drastically reduce viremia in HIV patients, ART must be continued throughout life, or else the virus rebounds from latently infected cells. Without a cure, the necessity of lifelong adherence to ART presents challenges of cost, toxicity, adverse interactions, and resistance. Recently, there have been several cases of HIV patients who underwent bone marrow transplant (BMT) and have shown a lack of viral rebound after discontinuing ART. One patient in Berlin received an allogeneic BMT from a donor who was homozygous for the HIV-resistant CCR5delta32 mutation, and two patients in Boston received allogeneic BMTs from CCR5-wildtype donors. The mechanism of possible cure in these patients has not been established, but an important similarity is that they all received allogeneic BMTs from unrelated donors. In cancer research, allogeneic BMTs and donor lymphocyte infusions (DLI) have been shown to reduce incidence of relapse in leukemia patients, likely due to a graft-versus-leukemia effect in which the donor immune cells recognize and clear the host's leukemic cells. One leading hypothesis in the Berlin and Boston patients is that a similar graft-versus-host effect occurred in which the donor immune cells recognized and cleared the host's HIV-infected cells, thus resulting in eradication of the HIV reservoir and cure. This proposal outlines specific aims to test this hypothesis using the humanized BLT mouse model developed in our laboratory. BLT mice are "humanized" by reconstitution with human hematopoietic cells, and they recapitulate key features of HIV infection, pathogenesis, suppression, and latency as seen in humans. The BLT mouse is thus an excellent model to investigate clearance of HIV-infected cells, and I will examine the graft-versus-host effect directly with allogeneic human DLI. These experiments will (1) evaluate the engraftment of allogeneic human DLI in already-humanized BLT mice and the clearance of existing human cells, particularly CD4+ T cells (primary HIV target cells) and resting CD4+ T cells (primary latently infected cells), and (2) evaluate the effet of allogeneic human DLI on HIV-infected cells in already-humanized HIV-infected BLT mice. If funded, this project will investigate a potential mechanism for curing HIV and will inform the future development of cure strategies, using an advanced humanized mouse model to perform experiments and analyses that would be impractical or unethical in human subjects. Along with the superb environment at UNC Chapel Hill, excellent mentoring by Dr. Garcia, and a well-rounded training plan, this research will provide a solid foundation on which I can continue my predoctoral training toward a career as a physician-scientist in the fields of immunology and infectious disease.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）仍然是全球发病率，死亡率和医疗保健成本的主要来源。仅在2011年，有3400万人患有艾滋病毒，有250万个新感染和170万人死亡。尽管抗逆转录病毒疗法（ART）可以大大降低艾滋病毒患者的病毒血症，但必须在一生中继续进行ART，否则，病毒反弹的病毒反弹。无法治愈，终身遵守艺术的必要性提出了成本，毒性，不良相互作用和抵抗的挑战。最近，有几例HIV患者接受了骨髓移植（BMT），并在中断ART后显示出缺乏病毒反弹。柏林的一名患者从供体的供体的同种异体BMT接受了同种异体BMT，该供体因抗HIV耐HIV的CCR5DELTA32突变而纯合子，波士顿的两名患者从CCR5-WildType供体中接受了同种异体BMT。这些患者可能治愈的机制尚未建立，但一个重要的相似之处在于，他们都从无关的供体中接受了同种异体BMT。在癌症研究中，已证明同种异体BMT和供体淋巴细胞输注（DLI）可以降低白血病患者复发的发生率，这可能是由于供体免疫细胞识别并清除宿主的白血病细胞的移植物 - 抗血清血症效应。柏林和波士顿患者中的一个主要假设是类似的移植物与宿主发生供体免疫细胞识别并清除宿主感染的HIV感染细胞的效果，从而消除了HIV储层和治愈。该提案概述了特定的旨在使用我们实验室中开发的人源化BLT小鼠模型检验这一假设。 BLT小鼠通过与人造血细胞重构“人性化”，并概括了人类中HIV感染，发病机理，抑制和潜伏期的关键特征。因此，BLT小鼠是研究HIV感染细胞清除率的绝佳模型，我将直接检查与同种异体人DLI直接检查移植物与宿主效应。 These experiments will (1) evaluate the engraftment of allogeneic human DLI in already-humanized BLT mice and the clearance of existing human cells, particularly CD4+ T cells (primary HIV target cells) and resting CD4+ T cells (primary latently infected cells), and (2) evaluate the effet of allogeneic human DLI on HIV-infected cells in already-humanized HIV-infected BLT mice.如果获得资助，该项目将研究一种潜在的治愈艾滋病毒的机制，并将使用先进的人源性小鼠模型进行治疗策略的未来开发，以执行实验和分析，这些实验和分析在人类受试者中是不切实际或不道德的。除了加西亚博士的出色指导以及一项全面的培训计划外，这项研究将为我可以在免疫学和感染性疾病领域的医师科学家身份继续我的职业生涯。