Genetic Predisposition and Pharmacogenomics of HIV-Associated Cognitive Impairment

HIV 相关认知障碍的遗传倾向和药物基因组学

• 批准号: 10712363
• 负责人: Heidi M. Crane
• 金额: $ 40.08万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10712363
• 关键词: AIDS dementia; Acquired Immunodeficiency Syndrome; Adherence; Adverse effects; Adverse event; Affect; Age; Aging; Alzheimer' s Disease; Astrocytes; Atherosclerosis; Biological; Biological Models; Bone necrosis; Brain; Caring; Cell Line; Cell model; Central Nervous System; Central Nervous System Infections; Chronic; Chronic Disease; Clinical; Clinical Data; Cognitive; Coin; Combined Modality Therapy; Complex; Computers; Consequences of HIV; Data; Delirium; Dementia; Development; Diagnosis; Digit structure; Disease; Dyslipidemias; Education; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Transcription; Genotype; HIV; HIV Infections; HIV-1; HIV-associated cognitive impairment; HIV-associated neurocognitive disorder; HIV/AIDS; Health behavior; Hepatotoxicity; Hypertension; Impaired cognition; Impairment; Individual; Infection; Inflammation; Integration Host Factors; Kidney; Kidney Diseases; Laboratories; Language; Life Expectancy; Liver diseases; Measures; Mental Depression; Microglia; Myocardial Infarction; Neurocognitive; Neurocognitive Deficit; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathogenicity; Pathway interactions; Performance; Persons; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Phenotype; Population; Prevention strategy; Process; Prospective cohort; Quality of life; Regimen; Reporting; Research; Research Support; Risk; Risk Factors; Role; Series; Stroke; System; Test Result; Testing; Unemployment; Variant; Viral; Virus; Virus Diseases; Work; adjudication; age related; antiretroviral therapy; brain health; clinical phenotype; cognitive function; cognitive testing; cohort; comorbidity; design; differential expression; drug efficacy; ethnic diversity; evidence base; gene network; genetic variant; genome-wide; health assessment; healthy aging; improved; individualized medicine; kidney dysfunction; neurocognitive disorder; neurocognitive test; neuroprotection; novel therapeutic intervention; parent grant; personalized medicine; phenotypic data; polygenic risk score; response; risk stratification; side effect; trait

SUMMARY With the introduction of potent antiretroviral therapy (ART), HIV is now manageable as a chronic disease, with improved life expectancy of people with HIV (PWH). However, despite viral suppression, high rates of comorbidities in PWH persist, due to a complex interplay between HIV, host genetics, inflammation, and chronic viral infections. Understanding the role of genetic susceptibility to common diseases or drug responses to ART could improve drug efficacy and reduce comorbidities. In our parent grant, we leveraged a large well- characterized prospective cohort of PWH in care in the U.S (CNICS, Centers for AIDS Research Network of Integrated Clinical Systems) with longitudinal clinical data to characterize the genetic landscape of a variety of comorbidities and adverse side effects associated with ART, including liver disease, kidney disease, atherosclerosis and osteonecrosis. However, in addition to these conditions, neurocognitive deficits also are a pronounced consequence of HIV/AIDS. HIV-1 infection targets the central nervous system and leads to high rates of delirium, depression, opportunistic central nervous system infections, and dementia. Long-term HIV replication in the brain occurs in astrocytes and microglia, allowing the virus to hide from ART and later compromise neuronal function. Cognitive impairment (CI) in PWH, culminating in Alzheimer's disease (AD), is becoming an increasingly important issue as this population ages. HIV-associated mild to moderate CI affects up to 50% PWH and results in lower quality of life, poorer adherence to medication, increased unemployment and reduced life expectancy. The pathogenic mechanisms causing CI are often multifactorial, including complex immunopathological processes controlled by HIV factors, the direct effects of ART, and genetic predisposition. This supplement will leverage CNICS and the extensive data generated by the parent grant to further understand genetic determinants of CI among PWH. We will use the digit symbol substitution neurocognitive test (DSST), widely used to measure CI due to brevity, reliability, and consistent performance across language, cultural and educational differences. We will: 1) Evaluate neurocognitive status in ethnically diverse PWH and identify genetic determinants of CI. We will oversee the completion of the DSST from the Brain Health Assessment, a computer-delivered, full cognitive assessment, in >1000 PWH with existing genome-wide genotype data and evaluate the relationship between their neurocognitive status and a series of polygenic risk scores for AD, dementias, and other cognitive traits. 2) Using systems pharmacology approach, identify biological pathways and related key driver genes through which various ART regimens may promote cognitive decline. We will treat neuronal cell lines with ART and search for the overlap between ART-induced transcriptional responses and gene networks associated with AD and dementias. Variants in the key driver genes will be evaluated in association with cognitive phenotypes in CNICS. This proposal is within the scope of the parent grant and will help generate new valuable phenotype data to advance the field of AD and dementia.

概括 随着引入有效的抗逆转录病毒疗法（ART），HI​​V现在可以作为一种慢性疾病来控制， 改善了艾滋病毒（PWH）患者的预期寿命。然而，尽管有病毒抑制，但 由于艾滋病毒，宿主遗传学，炎症和 慢性病毒感染。了解遗传易感性对常见疾病或药物反应的作用 艺术可以提高药物疗效并降低合并症。在我们的父母赠款中，我们利用了一个巨大的福祉 在美国，PWH的前瞻性PWH队列（CNICS，艾滋病中心，艾滋病中心 具有纵向临床数据的综合临床系统），以表征各种各样的遗传景观 合并症和与艺术相关的不良副作用，包括肝病，肾脏疾病， 动脉粥样硬化和骨坏死。但是，除了这些条件外，神经认知缺陷也是一个 艾滋病毒/艾滋病的明显后果。 HIV-1感染靶向中枢神经系统，并导致高 del妄，抑郁症，机会性中枢神经系统感染和痴呆症的发生率。长期艾滋病毒 大脑中的复制发生在星形胶质细胞和小胶质细胞中，使病毒躲藏在艺术和后来 妥协神经元功能。 PWH中的认知障碍（CI），最终在阿尔茨海默氏病（AD）中为 随着人口的年龄，成为越来越重要的问题。与HIV相关的轻度至中度CI影响 高达50％的PWH，导致生活质量较低，对药物的依从性较差，失业率增加 并降低预期寿命。引起CI的致病机制通常是多因素的，包括 由HIV因子控制的复杂免疫病理过程，ART的直接影响和遗传 倾向。该补充剂将利用CNIC和父母赠款生成的大量数据 进一步了解PWH中CI的遗传决定因素。我们将使用数字符号替换 神经认知测试（DSST），由于简洁，可靠性和一致性，用于测量CI 跨语言，文化和教育差异。我们将：1）在种族上评估神经认知状况 不同的PWH并确定CI的遗传决定因素。我们将监督DSST的完成 大脑健康评估是一种计算机保存，完整的认知评估，> 1000 PWH，现有 全基因组基因型数据并评估其神经认知状况与一系列的关系 AD，痴呆症和其他认知特征的多基因风险评分。 2）使用系统药理学方法， 确定各种艺术方案可以促进的生物途径和相关的关键驱动基因 认知能力下降。我们将使用艺术处理神经元细胞系，并寻找艺术引起的重叠 转录反应和与AD和痴呆症相关的基因网络。关键驱动程序中的变体 基因将与CNICS中的认知表型相关。该建议在 父母赠款将有助于生成新的有价值的表型数据，以推动AD和痴呆症的领域。