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

• 批准号: 8732200
• 负责人: Perry Meng-che Tsai
• 金额: $ 3.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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/8732200
• 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 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; Viremia; Virus; Virus Diseases; Work; anticancer research; antiretroviral therapy; cardiovascular disorder risk; career; cost; gene therapy; human subject; in vivo; innovation; leukemia; macrophage; monocyte; mortality; mouse model; peripheral blood; pre-doctoral; prevent; public health relevance; reconstitution; research study; viral DNA; viral RNA

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、死亡率和医疗费用的主要来源。仅 2011 年，就​​有 3400 万人感染艾滋病毒，新增感染者 250 万人，死亡人数 170 万人。尽管抗逆转录病毒疗法（ART）可以大大减少艾滋病毒患者的病毒血症，但必须终生持续进行抗逆转录病毒疗法，否则病毒会从潜伏感染的细胞中反弹。如果没有治愈方法， 终生坚持抗逆转录病毒治疗的必要性带来了成本、毒性、不良相互作用和耐药性方面的挑战。最近，有几例接受骨髓移植（BMT）的艾滋病毒患者在停止抗逆转录病毒治疗后没有出现病毒反弹。柏林的一名患者接受了 HIV 抗性 CCR5delta32 突变纯合捐赠者的同种异体 BMT，波士顿的两名患者接受了 CCR5 野生型捐赠者的同种异体 BMT。这些患者可能治愈的机制尚未确定，但一个重要的相似之处是他们都接受了来自无关捐赠者的同种异体 BMT。在癌症研究中，同种异体 BMT 和供体淋巴细胞输注 (DLI) 已被证明可以降低白血病患者的复发率，这可能是由于供体免疫细胞识别并清除宿主白血病细胞的移植物抗白血病效应。柏林和波士顿患者的一个主要假设是，类似的移植物抗宿主反应 捐赠者的免疫细胞识别并清除宿主的艾滋病毒感染细胞，从而消除艾滋病毒储存库并治愈艾滋病毒。该提案概述了具体 旨在使用我们实验室开发的人源化 BLT 小鼠模型来检验这一假设。 BLT 小鼠通过用人类造血细胞重建而“人性化”，它们重现了人类中所见的 HIV 感染、发病机制、抑制和潜伏期的关键特征。因此，BLT 小鼠是研究 HIV 感染细胞清除的绝佳模型，我将直接使用同种异体人类 DLI 来检查移植物抗宿主效应。这些实验将（1）评估同种异体人类 DLI 在已经人源化的 BLT 小鼠中的植入以及现有人类细胞的清除，特别是 CD4+ T 细胞（初级 HIV 靶细胞）和静息 CD4+ T 细胞（初级潜伏感染细胞），以及（2）评估同种异体人类 DLI 对已经人源化的 HIV 感染 BLT 小鼠中 HIV 感染细胞的影响。如果获得资助，该项目将研究治愈艾滋病毒的潜在机制，并为未来治疗策略的发展提供信息，使用先进的人性化小鼠模型进行在人类受试者中不切实际或不道德的实验和分析。北卡罗来纳大学教堂山分校的优越环境、加西亚博士的出色指导以及全面的培训计划，这项研究将为我继续我的博士前培训奠定坚实的基础，以成为免疫学和传染病领域的医师科学家。