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: 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
• 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

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）仍然是世界范围内发病率、死亡率和医疗费用的主要来源。仅2011年一年，就有3 400万人感染艾滋病毒，250万新感染者和170万人死亡。虽然抗逆转录病毒疗法（ART）可以大大减少艾滋病毒患者的病毒血症，但抗逆转录病毒疗法必须终生持续，否则病毒会从潜伏感染的细胞中反弹。没有解药，