Comparative Retroviral Epigenomics

比较逆转录病毒表观基因组学

• 批准号: 10115417
• 负责人: Sarah Adrianne LaMere
• 金额: $ 6.13万
• 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: 2018-03-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115417
• 关键词: Address; Animal Model; Animal Welfare; Area; Attention; Bioinformatics; Biometry; Brain; Cells; Chromatin; Clinical; Collaborations; Comparative Study; Complement; DNA; Data Analyses; Development; Epigenetic Process; Ethics; Evaluation; Exposure to; Funding; HIV; HIV Infections; HIV-1; Human; Immune system; In Vitro; Infection; Institution; Knowledge; Macaca; Medicine; Mentors; Methods; Modeling; Modification; Peripheral; Persons; Pharmaceutical Preparations; Play; Procedures; Proviruses; Publishing; RNA; Records; Reporting; Research; Research Design; Research Personnel; Retrovirology; Role; SIV; Sampling; Statistical Methods; T-Lymphocyte; Techniques; Technology; Testing; Time; Tissues; Training; United States National Institutes of Health; Virus; antiretroviral therapy; career development; comparative; effective therapy; epigenetic marker; epigenomics; experimental study; latent HIV reservoir; next generation sequencing; nonhuman primate; targeted treatment; therapeutic target; trial design; 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. Project Summary/Abstract Page 6

抽象的 尽管抗逆转录病毒疗法成功发展（ART），但期待已久的艾滋病毒治疗仍然没有 被发现。该病毒整合到整个身体的组织DNA中，并在 艺术制度。接受艺术的人无法停止使用药物，因为在大多数情况下，病毒都会 只需反弹艺术停止即可。找到治愈方法的一种方法是通过带来消除储层 该病毒从潜伏期中脱离，因此被感染的细胞可能被ART或宿主免疫系统杀死。表观遗传学 据信机制在逆转录病毒潜伏期中起着重要作用，但对表观遗传学知之甚少 与艾滋病毒潜在储层相关的标记。令人惊讶的是，SIV的发表量甚至更少 访问组织和感染的时间线可以更好地表征和控制。同时感染了SIV 猕猴是人类艾滋病毒感染的模型，不知道SIV和HIV是否知道 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治疗剂 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中的原病毒的比例，并包含 在艺术期间和在艾滋病毒感染的人类中终止艺术期间的抑制性表观遗传标记和 SIV感染的猕猴。此外，我将使用这些参数来评估与大小的关联 储层，与细胞相关的RNA和外周T细胞和大脑的ART停止后的病毒反弹， 这是一个特征较差的储层组织。这些研究将使我得出结论何种作用抑制作用 表观遗传标记在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有所不同。 重要的是，该项目将支持我作为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。拟议的培训将使我接触审判 设计和分析方法，包括生物统计学和生物信息学。这些方法对我至关重要 职业发展，因为我们现在非常依赖下一代测序技术，而 我希望进行的比较研究将需要了解研究设计的统计方法 数据分析。最后，这个项目将基于我在比较医学，逆转录病毒学和 表观遗传学。我将在1）临床表观遗传学技术中接受培训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）艾滋病毒研究的道德行为和5） 专业发展，包括授予技巧，建立合作和报告研究结果。 我的指导团队在所有拟议的培训领域中都有出色的记录，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。该提议建立在 先前的NIH资助研究并补充了当前的NIH资助项目。 项目摘要/摘要页面6