Extracellular Vesicle and Extracellular RNA Biomarkers of HIV-1 Central Nervous System Pathogenesis and Cigarette Use

HIV-1 中枢神经系统发病机制和香烟使用的细胞外囊泡和细胞外 RNA 生物标志物

• 批准号: 10217079
• 负责人: Kenneth W Witwer
• 金额: $ 63.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217079
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Astrocytes; Attention; Back; Benchmarking; Biological; Biological Markers; Biology; Brain; CD4 Positive T Lymphocytes; Catalogs; Categories; Cell Count; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Diagnosis; Diagnostic; Disease; Disease model; General Population; Goals; HIV; HIV antiretroviral; HIV-1; HIV-associated neurocognitive disorder; Human; Individual; Inflammation; Learning; Liquid substance; Literature; Longevity; Measurement; MicroRNAs; Microglia; Modeling; Molecular Profiling; Morbidity - disease rate; Morphologic artifacts; Nerve Degeneration; Neuraxis; Neurons; Pathogenesis; Phenotype; Plasma; Population; Process; RNA; RNA analysis; Reproducibility; Research; Role; Sampling; Smoking; Substance Use Disorder; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Tobacco smoking behavior; Tobacco use; Untranslated RNA; Validation; Vesicle; Viral Load result; antiretroviral therapy; body system; brain tissue; candidate identification; candidate marker; cigarette smoke; cigarette smoking; circular RNA; cohort; comorbidity; comparative; extracellular; extracellular vesicles; improved; innovation; nervous system disorder; nonhuman primate; novel; novel marker; prognostic; sample archive; senescence; tool; transcriptome sequencing; virology

ABSTRACT The HIV-associated neurocognitive disorders (HAND) and other neurologic disorders are predicted to affect a majority of HIV-infected individuals at some time during the lifespan. These disorders occur despite effective virologic suppression by antiretroviral therapy (ART). Yet few established biological markers. Recalling that plasma biomarkers developed for AIDS (viral load and CD4+ T cell count) were essential in developing treatment paradigms for AIDS, an intensified research focus on biomarkers of neurologic disease is warranted. Improved biomarkers may be particularly important when substance use disorders (SUDs) are comorbid with HIV disease. Among HIV+ individuals, cigarette smoking is several times more prevalent than in the general population and contributes to inflammation and senescence processes that exacerbate pathogenesis in multiple organ systems. Promising classes of biomarkers include stable extracellular RNAs (exRNAs), a portion of which are packaged into extracellular vesicles (EVs) that can leave tissue such as brain to be found in easily accessed biological fluids. These entities receive increasing attention as markers of neurologic disease because of roles in neurodegeneration and (for EVs) because they can be traced back to a cell or tissue of origin. Two categories of exRNA are particularly attractive because of their extraordinary stability: microRNAs (miRNAs) and circular RNAs (circRNAs). miRNAs have been studied in HIV disease and SUDs, but not in EVs of brain tissue, and almost nothing is known about circRNAs in HIV-1 pathogenesis or SUDs. In this project, we will develop a catalog of biomarkers of HIV-1 pathogenesis and cigarette use and identify how cigarette use may complicate interpretation of biomarker tests. Archived samples from a well characterized animal model and human cohorts will be tested to identify and validate candidate biomarkers. Our expertise is in HIV-1 disease and animal models; biomarkers of neurologic disease; EV techniques and biology; and noncoding RNAs. We will first use a novel tissue EV isolation technique to seek candidate molecular signatures of EVs and exRNA in brain tissue (Aim 1), and then investigate EV and exRNA signatures in matched, longitudinally collected cerebrospinal fluid and blood plasma (Aim 2). Importantly, Aim 3 investigates human samples in parallel. the project will address current gaps in the literature in rigorous and reproducible fashion by ruling out common artifacts of EV and exRNA analysis and through cutting edge confirmation of the identity of isolated EVs. Overall, we hypothesize that brain-derived EVs and their most stable exRNA cargo, miRNAs and circRNAs, serve as biomarkers of HIV-associated neurologic disorders. Since some markers will also be associated with cigarette smoking, tobacco use will be investigated for possible interfering effects on measurement of neurologic disease biomarkers.

摘要