Genetic Predisposition and Pharmacogenomics of HIV-Associated Cognitive Impairment

摘要 随着有效的抗逆转录病毒疗法(ART)的引入，艾滋病毒现在作为一种慢性病是可控的， 提高艾滋病毒感染者的预期寿命(PWH)。然而，尽管病毒受到抑制，但高发病率 由于HIV、宿主遗传学、炎症和感染之间的复杂相互作用，PWH的共病仍然存在。 慢性病毒感染。了解遗传易感性在常见疾病或药物反应中的作用 抗逆转录病毒治疗可提高药物疗效，减少并发症。在我们的父母资助中，我们利用了一大口井- 描述了美国护理中PWH的预期队列(CNICs，艾滋病研究中心网络 集成临床系统)，具有纵向临床数据，以表征各种 与抗逆转录病毒治疗相关的并发症和副作用，包括肝脏疾病、肾脏疾病、 动脉粥样硬化和骨坏死。然而，除了这些情况外，神经认知缺陷也是一种 艾滋病毒/艾滋病的显著后果。HIV-1感染以中枢神经系统为目标并导致高 精神错乱、抑郁、机会性中枢神经系统感染和痴呆症的发生率。长期的艾滋病毒 大脑中的复制发生在星形胶质细胞和小胶质细胞中，使病毒能够躲避ART和后来的病毒 神经功能受损。PWH中的认知障碍(CI)，最终导致阿尔茨海默病(AD)，是 随着人口老龄化，这一问题变得越来越重要。HIV相关的轻度至中度CI影响 高达50%的PWH，并导致较低的生活质量，较差的服药依从性，增加失业率 并缩短了预期寿命。引起CI的致病机制通常是多因素的，包括 由HIV因子、ART的直接影响和遗传因素控制的复杂免疫病理过程 性情。本补充资料将利用CNIC和母公司拨款生成的大量数据来 进一步了解PWH患者CI的遗传决定因素。我们将使用数字符号替换 神经认知测验(DSST)，因其简明、可靠和一致的表现而被广泛用于测量CI 跨越语言、文化和教育的差异。我们将：1)从种族角度评估神经认知状况 不同的PWH和识别CI的遗传决定因素。我们会从 大脑健康评估，一种计算机提供的全面认知评估，在&gt；1000 PWH中与现有 全基因组的基因数据，并评估他们的神经认知状态与一系列 阿尔茨海默病、痴呆和其他认知特征的多基因风险得分。2)运用系统药理学方法， 确定各种ART方案可能促进的生物途径和相关关键驱动基因 认知能力下降。我们将用ART处理神经细胞系，并寻找ART诱导的 与阿尔茨海默病和痴呆相关的转录反应和基因网络。关键驱动因素中的变体 基因将根据CNICs的认知表型进行评估。这项建议属于以下范围 父母提供资助，并将帮助产生新的有价值的表型数据，以促进AD和痴呆领域的发展。

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.