Comparative Retroviral Epigenomics

比较逆转录病毒表观基因组学

• 批准号: 10430170
• 负责人: Sarah Adrianne LaMere
• 金额: $ 12.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430170
• 关键词: AIDS clinical trial group; ATAC-seq; Address; Affect; Anatomy; Animal Model; Animal Welfare; Animals; Area; Attention; Bioinformatics; Biological; Biological Assay; Biometry; Blood; Blood specimen; Brain; Cells; Chromatin; Clinical; Collaborations; Comparative Study; Complement; Complex; Cytosine; DNA; DNA Methylation; Data; Data Analyses; Development; Epigenetic Process; Ethics; Evaluation; Exhibits; Exposure to; Familiarity; Funding; Genes; Gifts; Goals; Guidelines; HIV; HIV Infections; HIV-1; Histone Deacetylase Inhibitor; Human; Immune system; In Vitro; Individual; Infection; Institution; Interruption; Knowledge; Learning; Macaca; Measurement; Measures; Medical center; Medicine; Mentors; Methods; Methylation; Modeling; Modification; Monitor; Nebraska; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Play; Primates; Procedures; Proviruses; Publishing; RNA; Records; Reporting; Research; Research Design; Research Personnel; Retrovirology; Role; SIV; Sampling; Statistical Data Interpretation; Statistical Methods; System; T-Lymphocyte; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Training; Translating; Transposase; United States National Institutes of Health; Universities; Viral Load result; Virus; antiretroviral therapy; career development; cohort; comparative; computerized tools; effective therapy; epigenetic marker; epigenetic regulation; epigenomics; experimental study; genomic data; in vivo; insight; latent HIV reservoir; next generation sequencing; nonhuman primate; preference; promoter; responsible research conduct; sample collection; skills; targeted treatment; therapeutic target; trial design; viral DNA; viral RNA; viral rebound

Abstract Despite the successful development of antiretroviral therapies (ART), the long-awaited cure for HIV has still not been discovered. The virus integrates into DNA of tissues throughout the body and becomes latent after institution of ART. Persons receiving ART cannot discontinue their medications, as in most cases the virus will simply rebound upon ART cessation. One approach to finding a cure is to eliminate the reservoir by bringing the virus out of latency so that infected cells might be killed by ART or the host immune system. Epigenetic mechanisms are believed to play an important role in retroviral latency, yet little is known about the epigenetic markers associated with the latent reservoir for HIV. Surprisingly, even less has been published for SIV, where access to tissues and time lines of infection are better characterized and controlled. While SIV-infected macaques serve as a model for human HIV infection, there is no knowledge of whether SIV and HIV epigenetics have any similarity. To develop successful therapeutics that target epigenetic mechanisms of HIV latency, we must first identify these mechanisms and whether animal models will be suitable to test them. The proposed project will characterize the proportion of proviruses located in open chromatin and containing repressive epigenetic marks both during ART and after discontinuation of ART in HIV-infected humans and SIV-infected macaques. Further, I will use these parameters to evaluate the association with the size of the reservoir, cell-associated RNA, and viral rebound after ART cessation in both peripheral T cells and brain, which is a poorly characterized reservoir tissue. These studies will allow me to conclude what role repressive epigenetic marks play in proviral latency, and whether these mechanisms differ between tissues, and species. Importantly, this project will support my development as an independent researcher with expertise in clinical retroviral epigenetics and comparative research. The proposed training will provide me with exposure to trial design and analysis methods, including biostatistics and bioinformatics. These methods are critical to my career development, as we are now heavily reliant on next-generation sequencing technologies, and the comparative studies I wish to pursue will require an understanding of statistical methods for study design and data analysis. Finally, this project will build upon my background in comparative medicine, retrovirology, and epigenetics. I will receive training in 1) clinical epigenetics techniques 2) biostatistics and bioinformatics 3) non- human primate (NHP) procedures and NHP animal welfare 4) ethical conduct of HIV research and 5) professional development, including grantsmanship, building collaborations, and reporting research findings. My mentoring team includes an excellent track records in all proposed areas of training, including retrovirology, epigenetics, biostatistics, bioinformatics, and non-human primate SIV research. This proposal builds upon previous NIH funded research and complements current NIH funded projects.

抽象的 尽管抗逆转录病毒疗法（ART）已成功开发，但人们期待已久的艾滋病毒治疗方法仍未得到治愈。 被发现了。病毒整合到全身组织的 DNA 中，并在感染后潜伏。 艺术机构。接受 ART 的人不能停止用药，因为在大多数情况下，病毒会 停止 ART 后就会反弹。寻找治疗方法的一种方法是通过引入 病毒不再处于潜伏期，这样受感染的细胞可能会被 ART 或宿主免疫系统杀死。表观遗传 人们认为这些机制在逆转录病毒潜伏期中发挥着重要作用，但人们对表观遗传知之甚少。 与 HIV 潜伏病毒库相关的标记物。令人惊讶的是，针对 SIV 的发布甚至更少，其中 更好地表征和控制组织的获取和感染的时间线。当感染 SIV 时 猕猴作为人类艾滋病毒感染的模型，目前尚不清楚 SIV 和 HIV 是否 表观遗传学有任何相似之处。开发针对艾滋病毒表观遗传机制的成功疗法 潜伏期，我们必须首先确定这些机制以及动物模型是否适合测试它们。 拟议的项目将表征位于开放染色质并包含的原病毒的比例 在 HIV 感染者中，在 ART 期间和停止 ART 后都存在抑制性表观遗传标记， 感染 SIV 的猕猴。此外，我将使用这些参数来评估与大小的关联 ART 停止后外周 T 细胞和大脑中的储存库、细胞相关 RNA 和病毒反弹， 这是一个特征不明确的储存组织。这些研究将使我得出镇压的作用是什么 表观遗传标记在前病毒潜伏期中发挥作用，以及这些机制在组织和物种之间是否存在差异。 重要的是，这个项目将支持我作为一名具有临床专业知识的独立研究人员的发展 逆转录病毒表观遗传学和比较研究。拟议的培训将使我有机会接触试验 设计和分析方法，包括生物统计学和生物信息学。这些方法对我来说至关重要 职业发展，因为我们现在严重依赖下一代测序技术，并且 我希望进行的比较研究需要了解研究设计和研究的统计方法 数据分析。最后，这个项目将建立在我的比较医学、逆转录病毒学和 表观遗传学。我将接受以下方面的培训：1) 临床表观遗传学技术 2) 生物统计学和生物信息学 3) 非 人类灵长类动物 (NHP) 程序和 NHP 动物福利 4) HIV 研究的道德行为和 5) 专业发展，包括资助、建立合作和报告研究成果。 我的指导团队在所有拟议的培训领域都有出色的记录，包括逆转录病毒学、 表观遗传学、生物统计学、生物信息学和非人类灵长类动物 SIV 研究。该提案建立在 以前 NIH 资助的研究并补充了当前 NIH 资助的项目。