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).

我在神经活动和神经学研究经验的二十年中提出的项目工厂 免疫学，但涉及新的大胆投资线。这个新的方向不仅可以让我 为艾滋病毒/艾滋病研究做出贡献，但它也将有助于发展“病毒学”的新生领域，并确定其影响 阐明与药物使用相关的发病机理。我们所知的关键差距是 所有定义为“病毒蛋白”的病毒，用于HIV/AIDS发病机理，以及它是否与药物使用相关。 然而，由于对病毒研究的深度测序（也称为下一代测序）是最佳的病毒研究。 人类基因组DNA/RNA和病毒核酸的大小和抽象之间的巨大失衡。 此外，在中枢神经系统中访问感兴趣的大脑区域或CSF样品进行靶向病毒学研究 代表另一个主要障碍。我们已经开发了一种新颖的目标深度测序 在临床样品中检测整个病毒蛋白的平台，称为“ verofind”。该测定可以检测到所有561 已知感染人类的​​DNA或RNA病毒，可能是未被发现的病毒。与深度相比 Vierofind单独进行测序，可以富集存在多达127倍的脑样品中的病毒序列。 我们将定义大脑中的整个病毒蛋白，CSF和艾滋病毒/艾滋病患者有或没有吸毒的患者 使用Vierofind。这些包括已知病毒，病毒变异和潜在但未知病毒。我们将使用 几个同类艾滋病毒/艾滋病患者的库存样本，以及来自HIV+患者的CSF样本 拉什大学医学中心（RUMC）和我在赞比亚的全球神经病学计划。我们还将确定 病毒物种福尔马林固定，石蜡包裹的样品的表达模式，并表征其细胞 在大脑中的定位。 需要解决的主要挑战是超越病毒序列的表征， 并发展“病毒学”的新生领域。这将使我们能够将病毒学数据与 人类宿主中的基因组学，转录组学，代谢组学，免疫学和病理学使用系统 生物学方法，旨在定义可能的干预措施和治疗靶标。前卫机制 我将允许我利用我以前的研究成就和获得验收的收藏 在RUMC和赞比亚，样本以及艾滋病毒感染的患者有或不使用药物。它也适合 我担任RUMC神经病学系主任的新职位，将为我提供移动的自由 病毒学领域以一种真正变革的方式向前发展。通过将病毒学领域与其他“幻象”整合在一起 研究不仅会促进艾滋病毒/艾滋病和药物使用研究，而且还可以为描述可吸毒的方式铺平道路 靶标和开发病毒疾病的新型疗法。拟议的研究与 AIDS研究新的优先事项，包括HIV共同感染，合并症和并发症（CCC）。