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: 10407597
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407597
• 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; 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).

拟议的项目源于我在神经病毒学和神经病毒学领域二十年的研究经验 免疫学，而是涉及一种新的、大胆的研究路线，这个新方向不仅让我能够 为艾滋病毒/艾滋病研究做出贡献，但它也将有助于发展“病毒组学”这一新兴领域，并确定其影响 阐明与药物使用相关的发病机制是我们知识的主要空白。 所有病毒，定义为“病毒组”，涉及艾滋病毒/艾滋病的发病机制，以及是否与吸毒有关。 然而，单独的深度测序（也称为下一代测序）对于病毒研究而言并不是最佳选择，因为 人类基因组 DNA/RNA 和病毒核酸的大小和丰度之间存在巨大的不平衡。 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针对性病毒学研究 代表了另一个主要障碍。我们开发了一种新型的基于目标富集的深度测序。 用于检测临床样本中整个病毒组的平台，名为“ViroFind”，该检测可以检测所有 561 个病毒。 已知可感染人类的​​ DNA 或 RNA 病毒，以及与深层病毒相比，可能尚未发现的病毒。 仅通过测序，ViroFind 就可以将大脑样本中存在的病毒序列丰富至 127 倍。 我们将定义吸毒和未吸毒的艾滋病毒/艾滋病患者的大脑、脑脊液和血液中的整个病毒组， 我们将使用 ViroFind，其中包括已知病毒、病毒变种和可能未知的病毒。 储存了几组艾滋病毒/艾滋病患者的样本，以及来自在医院看到的艾滋病毒+患者的脑脊液样本 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、石蜡包埋的病毒物种的表达模式，以及表征其细胞 在大脑中的定位。 需要解决的主要挑战是超越病毒序列的单纯表征， 并发展“病毒组学”这一新兴领域，这将使我们能够将病毒学数据与病毒学数据整合在一起。 使用系统在人类宿主中进行基因组学、转录组学、代谢组学、免疫组学和病理学研究 生物学方法，旨在确定可能的干预措施和治疗目标。 将使我能够利用我以前的研究成果和我对尸检收集的访问权 RUMC 和赞比亚的样本以及吸毒或未吸毒的 HIV 感染患者队列也适用。 担任 RUMC 神经病学系主任的新职位，将使我能够自由地调整 通过将病毒组学领域与其他“组学”相结合，病毒组学领域以真正变革的方式向前发展。 研究不仅将推进艾滋病毒/艾滋病和药物使用研究，而且还为描述可药物性铺平道路 拟议的研究与办公室一致。 艾滋病研究的新重点包括艾滋病毒合并感染、合并症和并发症（CCC）。

项目成果

Characterization of the brain virome in human immunodeficiency virus infection and substance use disorder.

人类免疫缺陷病毒感染和物质使用障碍中脑病毒组的特征。

• 发表时间: 2024
• 影响因子: 3.7
• 作者: Dang, Xin;Hanson, Barbara A;Orban, Zachary S;Jimenez, Millenia;Suchy, Stephen;Koralnik, Igor J
• 通讯作者: Koralnik, Igor J