Genetic Predisposition and Pharmacogenomics of HIV-Associated Cognitive Impairment

总结 随着有效的抗逆转录病毒疗法（ART）的引入，艾滋病毒现在可以作为一种慢性疾病进行管理， 提高艾滋病毒感染者的预期寿命。然而，尽管病毒受到抑制， 由于HIV、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 ART可以提高药物疗效并减少合并症。在我们的母基金里，我们利用了一口大油井- 美国艾滋病研究网络中心（CNICS，Centers for AIDS Research Network， 整合临床系统）与纵向临床数据，以表征各种 与ART相关的合并症和不良副作用，包括肝病、肾病， 动脉粥样硬化和骨坏死。然而，除了这些条件，神经认知缺陷也是一个问题。 艾滋病毒/艾滋病的严重后果。HIV-1感染靶向中枢神经系统并导致高 谵妄、抑郁、机会性中枢神经系统感染和痴呆的发生率。长期HIV 在大脑中的复制发生在星形胶质细胞和小胶质细胞中，使病毒能够躲避ART， 损害神经元功能PWH中的认知障碍（CI），最终导致阿尔茨海默病（AD）， 随着人口老龄化，这成为一个越来越重要的问题。HIV相关的轻度至中度CI影响 高达50%的PWH，导致生活质量下降，药物依从性较差，失业率上升 和预期寿命的降低。导致CI的致病机制通常是多因素的，包括 由HIV因素控制的复杂免疫病理过程，ART的直接影响，以及遗传因素， 易感性该补充将利用CNICS和母基金产生的大量数据， 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、可靠和性能一致而广泛用于测量CI 跨越语言、文化和教育的差异。我们将：1）评估种族的神经认知状态 不同的PWH和确定CI的遗传决定因素。我们会从 脑健康评估，一种计算机提供的全面认知评估，在>1000 PWH中， 全基因组基因型数据，并评估他们的神经认知状态和一系列 AD、痴呆和其他认知特征的多基因风险评分。2)采用系统药理学方法， 确定各种ART方案可能促进的生物学途径和相关关键驱动基因 认知能力下降我们将用ART处理神经元细胞系，并寻找ART诱导的神经元细胞系之间的重叠。 转录反应和基因网络与AD和痴呆症。关键驱动因素的变化 将在CNICS中评估与认知表型相关的基因。该提案属于 该基金将帮助产生新的有价值的表型数据，以推进AD和痴呆症领域的研究。

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.