Contribution of the Virome to HIV/AIDS pathogenesis

病毒组对艾滋病毒/艾滋病发病机制的贡献

• 批准号: 10159233
• 负责人: Igor J Koralnik
• 金额: $ 79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-14 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159233
• 关键词: AIDS/HIV problem; Academic Medical Centers; Achievement; Acquired Immunodeficiency Syndrome; Address; Area; Biological Assay; Blood; Brain; Clinical; Collection; DNA Viruses; Data; Department chair; Drug usage; Formalin; Freedom; Genomic DNA; Genomics; HIV; Human; Intervention; Investigation; Knowledge; Mission; Names; National Institute of Drug Abuse; Neurology; Neurovirology; Nucleic Acids; Paraffin Embedding; Pathogenesis; Patients; Pattern; Positioning Attribute; Public Health; RNA; RNA Viruses; Research; Role; Sampling; Systems Biology; Variant; Viral; Virus; Virus Diseases; Zambia; base; co-infection; cohort; comorbidity; deep sequencing; detection platform; druggable target; experience; interest; metabolomics; neuroimmunology; next generation sequencing; novel; novel therapeutics; programs; stem; therapeutic target; transcriptomics; virology; virome

The proposed project stems from two decades of my research experience in Neuro-Virology and Neuro- Immunology, but involves a new and bold line of investigation. This new direction will allow me not only to contribute to HIV/AIDS research, but it will also help develop the nascent field of “Viromics, and define its impact to elucidate the pathogenesis associated with drug use. The key gap in our knowledge is the contribution of ALL viruses, defined as the “Virome”, to HIV/AIDS pathogenesis, and whether it is associated with drug use. However, deep sequencing alone (also called Next Gen sequencing) is sub-optimal for viral studies due to the enormous imbalance between size and abundance of human genomic DNA/RNA and viral nucleic acids. Furthermore, accessing brain areas of interest or CSF samples for targeted virological studies in the CNS represents another major obstacle. We have developed a novel target-enrichment deep sequencing-based platform for detection of the entire Virome in clinical samples, named “ViroFind”. This assay can detect all 561 DNA or RNA viruses known to infect humans, and potentially, yet undiscovered viruses. Compared to deep sequencing alone, ViroFind could enrich viral sequences present in brain samples up to 127-fold. We will define the entire Virome in the brain, CSF and blood of HIV/AIDS patients with and without drug use, using ViroFind. These include known viruses, viral variants and potentially yet unknown viruses. We will use banked samples of several cohorts of HIV/AIDS patients, as well as CSF samples from HIV+ patients seen at Rush University Medical Center (RUMC) and at my Global Neurology Program in Zambia. We will also determine the expression pattern of viral species formalin-fixed, paraffin-embedded samples, and characterize their cellular localization in the brain. The major challenge that needs to be addressed is to go beyond the mere characterization of viral sequences, and to develop the nascent field of “Viromics”. This will allow us to integrate virological data together with genomics, transcriptomics, metabolomics, immunomics and pathobiology in the human host using a systems biology approach, aiming to define possible interventions and therapeutic targets. The Avant-Garde mechanism will allow me to leverage my previous research achievements and my access to collections of post mortem samples as well cohorts of HIV-infected patients with and without drug use at RUMC and Zambia. It is also suited to my new position as Chair of Department of Neurology at RUMC, and will give me the freedom to move the field of Viromics forward in a truly transformative way. By integrating the field of Viromics with other “omics” these studies will not only advance HIV/AIDS and drug use research, but also pave the way for delineating druggable targets and developing novel therapies for viral diseases. The proposed studies are in line with the Office of AIDS Research new priorities including HIV co-infections, co-morbidities and complications (CCC).

这个提议的项目源于我二十年来在神经病毒学和神经病学方面的研究经验。 免疫学，但涉及一条新的大胆的调查路线。这一新方向将使我不仅能够 为艾滋病毒/艾滋病研究做出贡献，但它也将有助于发展新生的“病毒学”领域，并确定其影响 目的：阐明与药物使用有关的发病机制。我们知识中的关键差距是 所有病毒，定义为“病毒体”，与艾滋病毒/艾滋病的发病机制，以及它是否与药物的使用有关。 然而，单独的深度测序(也称为下一代测序)对于病毒研究来说是次优的，因为 人类基因组DNA/RNA和病毒核酸的大小和丰度之间的巨大不平衡。 此外，获取感兴趣的大脑区域或脑脊液样本以进行中枢神经系统的靶向病毒学研究 代表着另一个主要障碍。我们开发了一种基于深度测序的新型靶向富集法 用于检测临床样本中的整个病毒体的平台，名为“ViroFind”。这项检测可以检测到全部561个 已知可感染人类的DNA或RNA病毒，以及潜在的尚未发现的病毒。与深度相比 仅测序一项，ViroFind就可以使大脑样本中的病毒序列丰富127倍。 我们将确定艾滋病毒/艾滋病患者的大脑、脑脊液和血液中的整个病毒群， 使用ViroFind。这些病毒包括已知的病毒、病毒变种和潜在的未知病毒。我们将使用 储存了几组艾滋病毒/艾滋病患者的样本，以及艾滋病毒+患者的脑脊液样本，见 拉什大学医学中心(RUMC)和我在赞比亚的全球神经病学项目。我们还将确定 福尔马林固定、石蜡包埋的病毒株的表达模式及其细胞特性 大脑中的定位。 需要解决的主要挑战是超越单纯的病毒序列特征， 并开发“病毒学”这一新兴领域。这将使我们能够将病毒学数据与 基因组学、转录组学、代谢组学、免疫组学和病理生物学 生物学方法，旨在确定可能的干预措施和治疗目标。先锋机制 将使我能够利用我以前的研究成果和我对尸检收藏的访问 样本以及在RUMC和赞比亚使用和不使用药物的艾滋病毒感染患者的队列。它也很适合 我担任RUMC神经科主任的新职位，并将给我自由移动的自由 病毒学领域以一种真正变革性的方式向前发展。通过将病毒学领域与其他“组学”领域结合起来 研究不仅将推动艾滋病毒/艾滋病和药物使用的研究，而且还将为划定可毒品的范围铺平道路。 目标和开发针对病毒疾病的新疗法。拟议的研究与办公室的研究是一致的 艾滋病研究新的优先事项，包括艾滋病毒合并感染、共病和并发症(CCC)。