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）：尽管抗逆转录病毒治疗长期抑制了循环病毒，但HIV-1储库仍以潜伏形式存在。实现治愈HIV-1感染的主要挑战是这些潜伏病毒储库的持续存在。迄今为止，只有一种HIV-1感染的功能性“治愈”，即在接受清髓性异基因造血干细胞移植治疗急性髓性白血病的个体中，供体细胞缺乏功能性CCR 5，CCR 5是HIV-1进入宿主细胞所使用的辅助受体。移植前细胞毒性化疗减少HIV-1储库可能有助于病毒根除;然而，细胞毒性化疗联合或不联合造血干细胞移植（HSCT）对病毒储库和宿主因子以及免疫应答的影响在很大程度上尚不清楚。我们的研究将为HIV-1的持续存在和演变提供更深入的了解，这将对旨在消除HIV宿主的治疗方法产生实际影响。我们建议研究细胞毒化疗和/或HSCT对HIV-1感染的血液系统恶性肿瘤患者启动全身抗肿瘤治疗时病毒库大小、演变和免疫功能的影响。我们假设，细胞毒性化疗或HSCT减少了潜伏感染细胞的池，并将表现为总的和整合的HIV-1 DNA的量的长期减少。我们还假设，在细胞减少治疗后的免疫重建过程中没有显着的演变，但HIV-1 DNA的减少和随后的CD 4+淋巴细胞亚群和其他组织室的再扩增可能会导致剩余病毒库的多样性发生变化。该提案的具体目的包括：1）研究化疗或HSCT治疗恶性血液病对外周血和骨髓储库大小的影响，2）研究化疗前后残留病毒血症、淋巴细胞活化和HIV特异性免疫应答的变化，3）研究细胞毒性化疗对HIV-1演变、组织区室化和储库多样性的影响。这项为期五年的研究将利用创新的方法来研究水库动态，如454深度测序和测定，以检测和量化宿主组织和血浆病毒血症中低于标准检测限的低水平HIV-1 DNA。淋巴细胞活化、宿主进入因子和艾滋病毒特异性免疫的措施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布里格姆妇女医院（BWH）传染病科的医学讲师，并计划进一步培训，这将导致在转化病毒学和以患者为导向的研究方面的独立学术生涯。该项目将在BWH的丹尼尔·库里茨克斯博士和曼尼什萨加尔博士的指导下进行。