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: 9126930
• 负责人: Timothy Jensen Henrich
• 金额: $ 7.37万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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/9126930
• 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(申请人提供)：尽管长期使用抗逆转录病毒疗法抑制循环病毒，HIV-1储存库仍然以潜伏的形式存在。实现治愈艾滋病毒-1感染的主要挑战是这些潜伏的病毒库的持久性。到目前为止，只有一个人接受了急性髓系白血病清髓性异基因造血干细胞移植，但供体细胞缺乏功能性CCR5，HIV-1利用CCR5进入宿主细胞，从而有效地治愈了HIV-1感染。移植前细胞毒性化疗减少HIV-1病毒贮存库可能有助于病毒的根除；然而，细胞毒性化疗加或不加造血干细胞移植(HSCT)对病毒贮存库、宿主因子和免疫反应的影响在很大程度上尚不清楚。我们的研究将为HIV-1的持久性和进化提供更多的洞察力，这将对旨在消除HIV宿主的治疗具有实际意义。我们建议研究细胞毒性化疗和/或造血干细胞移植对HIV-1感染的血液系统恶性肿瘤患者的病毒库大小、进化和免疫功能的影响，以启动系统抗肿瘤治疗。我们假设，细胞毒性化疗或HSCT减少了潜伏感染细胞池，并将表现为HIV-1DNA总量和整合的长期减少。我们还假设，在细胞减少治疗后的免疫重建过程中没有显著的进化，但HIV-1DNA的减少以及随后CD4+淋巴细胞亚群和其他组织亚群的重新扩张可能会导致剩余病毒库的多样性发生变化。这一建议的具体目的包括：1)研究血液系统恶性肿瘤化疗或造血干细胞移植对外周血和骨髓库大小的影响；2)研究化疗前后残留病毒血症、淋巴细胞活化和HIV特异性免疫反应的变化；3)研究细胞毒化疗对HIV-1进化、组织分区和库多样性的影响。这项为期五年的研究将利用创新的方法来研究宿主动态，例如454深度测序和分析，以检测和量化宿主组织中的低水平艾滋病毒-1 DNA和低于标准测试检测极限的血浆病毒血症。与免疫学家和进化病毒学家合作，淋巴细胞激活、宿主进入因子和艾滋病毒特异性免疫的测量也将被纳入研究计划。这位候选人目前是哈佛医学院布里格姆和妇女医院(BWH)传染病科的医学讲师，并计划进行进一步的培训，以在翻译病毒学和以患者为导向的研究方面取得独立的学术生涯。该项目将在BWH的Daniel Kuritzkes博士和Manish Sagar博士的指导下进行。