Impact of Chemotherapy and Stem Cell Transplant on HIV-1 Reservoir Dynamics

化疗和干细胞移植对 HIV-1 储库动态的影响

• 批准号: 8606807
• 负责人: Timothy Jensen Henrich
• 金额: $ 13.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606807
• 关键词: Academic Medical Centers; Acute Myelocytic Leukemia; Aftercare; Allogenic; Autologous; Biological Assay; Blood; Bone Marrow; Bone Marrow Cells; Bone Marrow Purging; CCR5 gene; CD34 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cells; Chronic; Collaborations; Communicable Diseases; Cytotoxic Chemotherapy; DNA; Dendritic Cells; Detection; Disease; Engraftment; Evolution; HIV; HIV-1; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Hospital Planning; Hospitals; Housing; Immune; Immune response; Immunity; Immunologist; Impairment; Individual; Infection; Integration Host Factors; Knowledge; Lead; Lymphocyte Activation; Lymphocyte Subset; Measures; Medicine; Memory; Mentorship; Modality; Morbidity - disease rate; Mutation; Myeloablative Chemotherapy; Myelogenous; Patients; Peripheral; Phylogenetic Analysis; Plasma; Play; Population; Research; Residual state; Role; Stem cell transplant; Testing; Therapeutic; Time; Tissue Donors; Tissues; Training; Transplantation; Transplanted tissue; V3 Loop; Variant; Viral; Viremia; Virus; Woman; antiretroviral therapy; cancer therapy; career; cell type; chemotherapy; cohort; cytotoxicity; deep sequencing; graft vs host reaction; immune function; innovation; insight; instructor; medical schools; monocyte; mortality; neoplastic; novel therapeutics; patient oriented research; peripheral blood; prospective; receptor; reconstitution; viral RNA; virology

DESCRIPTION (provided by applicant): HIV-1 reservoirs continue to exist in latent form despite long-term suppression of circulating virus with antiretroviral therapy. The main challenge in achieving a cure for HIV-1 infection is the persistence of these latent viral reservoirs. To dat, there has only been one functional "cure" of HIV-1 infection in an individual who underwent myeloablative allogeneic hematopoietic stem cell transplant for acute myeloid leukemia with donor cells lacking functional CCR5, a co-receptor used by HIV-1 to enter host cells. Reduction of HIV-1 reservoirs with pre-transplant cytotoxic chemotherapy likely contributed to viral eradication; however, the effects of cytotoxic chemotherapy with or without hematopoietic stem cell transplant (HSCT) on the viral reservoir and host factors and immune responses are largely unknown. Our study will provide greater insight into the persistence and evolution of HIV-1 that will have practical implications for therapeutics aimed at eliminating HIV reservoirs. We propose to investigate the effect of cytotoxic chemotherapy and/or HSCT on viral reservoir size, evolution, and immune function in HIV-1 infected individuals with hematologic malignancies initiating systemic anti-neoplastic therapy. We hypothesize that cytotoxic chemotherapy or HSCT reduces pools of latently infected cells, and will be manifested as a long-term reduction in the amount of total and integrated HIV-1 DNA. We also hypothesize that there is no significant evolution during immune reconstitution following cytoreductive therapy, but reductions in HIV-1 DNA and subsequent re-expansion of CD4+ lymphocyte subsets and other tissue compartments may lead to changes in the diversity of the remaining viral reservoir. Specific aims of this proposal include: 1) investigate the effects of chemotherapy or HSCT for hematologic malignancy on peripheral blood and bone marrow reservoir size, 2) study the changes in residual viremia, lymphocyte activation, and HIV-specific immune responses before and after chemotherapy, and, 3) investigate the effects of cytotoxic chemotherapy on HIV-1 evolution, tissue compartmentalization, and reservoir diversity. This five-year study will utilize innovative approaches to investigate reservoir dynamics such as 454 deep sequencing and assays to detect and quantify low levels of HIV-1 DNA from host tissue and plasma viremia below the limit of detection of standard tests. Measures of lymphocyte activation, host-entry factors and HIV-specific immunity will also be integrated into the research plan in collaboration with immunologists and evolutionary virologists. The candidate is currently an Instructor of Medicine at Harvard Medical School in the Division of Infectious Diseases at the Brigham and Women's Hospital (BWH), and plans on further training that will lead to an independent academic career in translational virology and patient-oriented research. This project will be conducted under the mentorship of Dr. Daniel Kuritzkes and Dr. Manish Sagar at the BWH.

描述（由申请人提供）：尽管长期抑制了抗逆转录病毒疗法的循环病毒，但HIV-1储层仍以潜在形式存在。实现HIV-1感染治疗的主要挑战是这些潜在病毒储存库的持久性。在DAT上，在一个人中，仅接受过一种功能性的HIV-1感染功能性“治愈”，该个体接受了脊髓含量的同种异体造血干细胞移植，用于急性髓细胞性白血病，缺乏功能性CCR5，该供体细胞（一种供体CCR5）（一种由HIV-1使用的共受体CCR5）用于输入宿主细胞。用移植前细胞毒性化学疗法减少HIV-1储层可能会导致病毒消除。然而，有或没有造血干细胞移植（HSCT）对病毒储量和宿主因子和免疫反应的细胞毒性化疗的影响在很大程度上尚不清楚。我们的研究将对HIV-1的持久性和演变提供更深入的了解，这将对旨在消除HIV储层的治疗学具有实际影响。我们建议研究细胞毒性化学疗法和/或HSCT对HIV-1感染患有血液学恶性肿瘤的患者的病毒储量大小，进化和免疫功能的影响。我们假设细胞毒性化学疗法或HSCT减少了潜在感染细胞的池，并将表现为总体和整合HIV-1 DNA的长期减少。我们还假设在细胞减少治疗后免疫重建过程中没有明显的演变，但是HIV-1 DNA的降低以及随后的CD4+淋巴细胞亚群和其他组织室的重新扩张可能会导致剩余病毒储量的多样性变化。 Specific aims of this proposal include: 1) investigate the effects of chemotherapy or HSCT for hematologic malignancy on peripheral blood and bone marrow reservoir size, 2) study the changes in residual viremia, lymphocyte activation, and HIV-specific immune responses before and after chemotherapy, and, 3) investigate the effects of cytotoxic chemotherapy on HIV-1 evolution, tissue compartmentalization, and储层多样性。这项为期五年的研究将利用创新方法研究储层动力学，例如454深度测序和测定，以检测和量化低于标准测试检测限的宿主组织和血浆病毒血症的低水平HIV-1 DNA。淋巴细胞激活，宿主入学因素和HIV特异性免疫的测量也将与免疫学家和进化病毒学家合作纳入研究计划。 该候选人目前是哈佛医学院的医学教练，在杨百翰和妇女医院（BWH）的传染病科，并计划进一步培训，这将导致转化病毒学和面向患者的研究独立学术职业。该项目将在BWH的Daniel Kuritzkes博士和Manish Sagar博士的指导下进行。