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: 10076416
• 负责人: Igor J Koralnik
• 金额: $ 71.73万
• 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/10076416
• 关键词: Contribution; Virome; HIV; AIDS; pathogenesis

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).

该项目的提出源于我在神经病毒学和神经学方面20年的研究经验， 免疫学，但涉及一个新的和大胆的调查路线。这个新的方向将使我不仅能够 它有助于艾滋病毒/艾滋病的研究，但它也将有助于发展“病毒组学”的新兴领域，并确定其影响 以阐明与吸毒相关的发病机制。我们知识的关键差距在于 ALL病毒，定义为“病毒组”，对HIV/AIDS的致病作用，以及它是否与吸毒有关。 然而，单独的深度测序（也称为下一代测序）对于病毒研究来说是次优的，这是由于 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，进入感兴趣的脑区或CSF样本用于CNS中的靶向病毒学研究， 这是另一个主要障碍。我们开发了一种新的基于靶富集的深度测序方法， 用于检测临床样品中的整个病毒组的平台，称为“ViroFind”。该检测方法可以检测所有561个 已知感染人类的DNA或RNA病毒，以及潜在的尚未发现的病毒。相比之下， 单独测序，ViroFind可以富集大脑样本中存在的病毒序列高达127倍。 我们将定义有和没有吸毒的艾滋病毒/艾滋病患者的大脑、脑脊液和血液中的整个病毒组， 使用ViroFind。这些病毒包括已知病毒、病毒变体和潜在的未知病毒。我们将使用 几个HIV/AIDS患者队列的库存样本，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项目。我们还将确定 病毒种福尔马林固定、石蜡包埋样品的表达模式，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简单表征， 并发展“病毒组学”这一新兴领域。这将使我们能够整合病毒学数据， 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靶点。先锋机制 将使我能够利用我以前的研究成果和我对死后尸体的收集 在RUMC和赞比亚，使用和不使用药物的HIV感染患者的样本和队列。它也适合 我作为RUMC神经病学系主任的新职位，并将给我自由移动 以一种真正变革性的方式向前发展。通过将病毒组学领域与其他“组学”相结合， 这些研究不仅将推进艾滋病毒/艾滋病和药物使用研究，而且还为划定可药用药物铺平了道路。 靶点和开发病毒性疾病的新疗法。拟议的研究符合人权高专办的要求， 艾滋病研究新的优先事项，包括艾滋病毒合并感染，合并症和并发症（CCC）。