Evaluation of Neurobiological Mechanisms Mediating the Effect of Immune Activation on Neurocognitive Impairment and the Role of Psychosocial Factors Among Women Living with HIV

免疫激活对神经认知障碍影响的神经生物学机制的评估以及女性艾滋病毒感染者心理社会因素的作用

• 批准号: 10704105
• 负责人: Andrea Norcini Pala
• 金额: $ 67.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-13 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704105
• 关键词: Address; Adherence; Affect; Age; Aging; Attention; Behavior Therapy; Behavioral; Biological; Biological Markers; Chronic; Chronic stress; Clinical; Cognitive; Data; Development; Discrimination; Dopamine; Dopamine Uptake Inhibitors; Etiology; Evaluation; Goals; HIV; Hair; Immune; Immunologic Markers; Immunotherapy; Impaired cognition; Individual; Individual Differences; Inflammatory; Infrastructure; Interleukin-6; Intervention; Knowledge; Learning; Letters; Life; Light; Link; Longitudinal Studies; Mediating; Mental Depression; Mental Health; Metabolism; Neurobiology; Neurocognitive Deficit; Neurons; Neuropsychology; Neurotransmitters; Norepinephrine; Outcome; Pathway interactions; Persons; Phenotype; Phenylalanine; Prevention; Psychosocial Factor; Quinolinic Acid; Risk; Risk Factors; Role; Serotonin; Short-Term Memory; Social support; Specimen; TNF gene; Time; Treatment/Psychosocial Effects; Tryptophan; Viral; Woman; Women' s Group; Women' s Interagency HIV Study; Work; aged; antiretroviral therapy; biopsychosocial; cognitive function; cost effective; executive function; experience; high risk; immune activation; immunoregulation; improved; marginalization; men; multi-component intervention; negative affect; nerve injury; neurobiological mechanism; neurofilament; neurotoxic; pharmacologic; psychosocial; public health priorities; racial diversity; resilience; sex; social stigma; substance use; therapy adherence

PROJECT ABSTRACT/SUMMARY. The proposed R01 is built upon the premise that: 1) Cognitive impairment (CI) persists even in the context of HIV viral suppression; 2) women living with HIV (WLWH) experience disproportionate burden of CI and have higher rates of, and stronger associations with, many of the underlying biopsychosocial risk factors for CI, as well as unique sex-specific risk factors; 3) immune activation persists in the context of viral suppression; 4) immune activation (e.g., Interleukin[IL]-6, sCD163) is a consistent risk factor of CI in HIV; 5) neurobiological pathways affecting cognitive functions are activated by HIV directly and indirectly through immune activation; 6) psychosocial factors such as stigma/discrimination, depression, and substance use impair cognitive functions and are associated with heightened immune activation, likely both directly and indirectly through reduced ART levels. By leveraging the strong infrastructure of the Women's Interagency HIV Study (WIHS), including existing behavioral data and specimen, the current longitudinal study will fill significant gaps in the field by examining the role of the neurobiological pathways whereby chronic immune activation leads to CI phenotypes in a large phenotypically well-defined group of WLWH. In a highly cost-effective approach, we will use existing biospecimen to assess biomarkers of chronic immune activation and neurobiological pathways and link them to existing neuropsychological assessments among N=500 WLWH aged 26 and older (Median age = 50) at 3 time points, to assess the following aims: Aim 1. To examine neurobiological pathways mediating the link between chronic immune activation and CI phenotypes in WLWH. Aim 2. To identify psychosocial factors affecting immune activation and neurobiological pathways. Aim 3. To examine the role of ART hair levels in mediating the effect of psychosocial factors in Aim 2 on immune activation and neurobiological pathway biomarkers. Impact. The results of this study will have several important clinical implications for the prevention and treatment of CI in WLWH, including behavioral and pharmacological therapies. Understanding the unique impact of biomarkers on cognitive outcomes will provide guidance on clinical intervention targets (e.g., immune therapy, dopamine reuptake inhibitors). Understanding the role of psychosocial factors in modulating immune activation and neurobiological pathways and the mediating role of ART adherence level, will inform behavioral intervention strategies (e.g., resilience, social support). Psychosocial factors may be particularly ideal intervention targets to curb the inflammatory cascade leading to CI.

项目摘要/总结。拟议的 R01 的前提是： 1) 认知障碍 (CI) 即使在 HIV 病毒抑制的情况下也仍然存在； 2) 女性艾滋病毒感染者 (WLWH) 的经历 CI 的负担不成比例，并且与许多潜在的因素有更高的发生率和更强的关联 CI 的生物心理社会风险因素，以及独特的性别风险因素； 3）免疫激活持续存在 病毒抑制的背景； 4) 免疫激活（例如白介素[IL]-6、sCD163）是一致的危险因素 HIV 中 CI 的影响； 5）影响认知功能的神经生物学途径被HIV直接和间接激活 通过免疫激活； 6) 社会心理因素，例如耻辱/歧视、抑郁和物质 使用损害认知功能并与增强的免疫激活相关，可能直接和 间接通过降低 ART 水平。通过利用妇女机构间强大的基础设施 HIV研究（WIHS），包括现有的行为数据和样本，目前的纵向研究将 通过检查神经生物学途径的作用填补了该领域的重大空白 免疫激活导致大量表型明确的 WLWH 群体出现 CI 表型。在一个 极具成本效益的方法，我们将使用现有的生物样本来评估慢性免疫的生物标志物 激活和神经生物学途径，并将它们与现有的神经心理学评估联系起来 N=500 名 26 岁及以上的 WLWH（中位年龄 = 50）在 3 个时间点，以评估以下目标： 目标 1. 检查介导慢性免疫激活和 CI 表型之间联系的神经生物学途径 WLWH。目标 2. 确定影响免疫激活和神经生物学途径的社会心理因素。目的 3. 检查 ART 毛发水平在调节目标 2 中心理社会因素对免疫的影响中的作用 激活和神经生物学途径生物标志物。影响。这项研究的结果将有几个重要意义 预防和治疗 WLWH 中 CI 的临床意义，包括行为和药理学 疗法。了解生物标志物对认知结果的独特影响将为以下方面提供指导： 临床干预目标（例如免疫治疗、多巴胺再摄取抑制剂）。了解角色 调节免疫激活和神经生物学途径的心理社会因素及其中介作用 ART 依从水平将为行为干预策略（例如，复原力、社会支持）提供信息。社会心理 因子可能是抑制导致 CI​​ 的炎症级联反应的特别理想的干预目标。