Mental Health and Cognition in HIV Infection in Rakai Uganda

包括抑郁症和神经认知障碍(NCI)在内的精神健康障碍是最常见的中枢 尽管有效的抗逆转录病毒治疗(ART)，但艾滋病毒感染的神经系统(CNS)并发症。据估计， 40-50%的HIV+患者至少有一种精神健康障碍。乌干达，亚伯拉罕的一个低收入国家 撒哈拉非洲(SSA)约有150万艾滋病毒携带者(PLWH)，其中许多人接受抗逆转录病毒治疗。尽管有艺术 使用中，中枢神经系统并发症在PLWH中持续存在，这是显著的异质性。乌干达提供了一个独特的 为增进我们对严重抑郁障碍[MDD]和NCI的理解而设置的环境，因为 在美国的令人困惑的情况，如脑血管疾病风险因素和非法药物使用(例如， 毒品、可卡因)在乌干达很少见。我们建议解决的最重要的假设是 PLWH中MDD和NCI的显著异质性以及心理社会决定因素(例如，性和身体) 创伤、暴力)可能是造成这种异质性的原因。解决MDD和NCI中的异构性是 对促进我们对认知表型的理解至关重要。为了达到我们的目的，我们将用一本小说 艾滋病毒研究中精神健康的方法论，NIMH研究领域标准(RDoC)框架， 认识到异质性，首先检查PLWH的行为表型，然后研究 了解这些表型的功能后果和潜在的病理生理学 表型。我们的研究结果应该会导致更准确的诊断、预后和有针对性的干预 全球艾滋病毒感染中的MDD和NCI。我们计划以经济高效的方式利用现有的基础设施和 来自我们之前的Rakai神经病学队列研究的数据，以检查以下目标：目标1：检查单独 HIV和心理社会决定因素对PLWH患者中枢神经系统功能障碍的交互作用。Hyp 1.暴露于 性/身体创伤或暴力将与这一人群中的艾滋病毒相互作用，并将与更多的 陈述性记忆、认知控制和NVS的损害/下降。目标2：检查心理社会的影响 决定因素和中枢神经系统功能障碍对PLWH患者ART依从性的影响。Hyp 2.暴露于性/身体创伤或 暴力和/或陈述性记忆、认知控制和NVS的损害/下降将对ART产生不利影响 坚持不懈。探索性目标3：确定与中枢神经系统功能障碍最密切和最可靠的生物标志物 在艾滋病毒和/或心理社会决定因素的背景下。Hyp 3：神经元损伤的不同生物标志物和 中枢神经系统炎症将与陈述性记忆、认知控制、运动、 在艾滋病毒和/或受到性/身体创伤或暴力的情况下感染和NVS。我们还将建设能力 评估和开展精神健康障碍的研究，并引入新的措施，以坚持我们的 一群人。我们的提案涉及美国国立卫生研究院艾滋病研究办公室的几个高度优先的研究课题，包括 HIV相关的合并症，了解HIV中精神健康障碍发病机制的基础研究 感染，以及确定可能治愈艾滋病毒感染的病毒库的研究。

Mental health disorders including depression and neurocognitive impairment (NCI) are the most common central nervous system (CNS) complications of HIV infection despite effective antiretroviral therapy (ART). It is estimated that 40-50% of HIV+ individuals have at least one mental health disorder. Uganda, a low-income country in Sub- Saharan Africa (SSA) has ~1.5 million people living with HIV (PLWH) many of whom are on ART. Despite ART use, CNS complications, which are notably heterogeneous, persist among PLWH. Uganda provides a unique setting for advancing our understanding of major depressive disorder [MDD] and NCI, because common confounding conditions in the United States such as cerebrovascular disease risk factors and illicit drug use (e.g., narcotics, cocaine) are rare in Uganda. We propose to address the overarching hypothesis that there is substantial heterogeneity in MDD and NCI in PLWH and that psychosocial determinants (e.g., sexual and physical trauma, violence) are likely contributors to this heterogeneity. Addressing the heterogeneity in MDD and NCI is critical to advancing our understanding of cognitive phenotypes. To accomplish our aims, we will use a novel methodology for mental health in HIV research, the NIMH Research Domain Criteria (RDoC) framework, which recognizes heterogeneity, to first examine behavioral phenotypes among PLWH followed by studies to understand the functional consequences of these phenotypes and the underlying pathophysiology in these phenotypes. Our study results should lead to more accurate diagnosis, prognosis, and targeted interventions for MDD and NCI in HIV infection globally. We plan to cost-effectively leverage the established infrastructure and data from our previous Rakai Neurology Cohort Study to examine the following aims: Aim 1: Examine separate and interactive effects of HIV and psychosocial determinants on CNS dysfunction in PLWH. Hyp 1. Exposure to sexual/physical trauma or violence will interact with HIV in this population and will be associated with greater impairments/decline in declarative memory, cognitive control, and NVS. Aim 2: Examine effects of psychosocial determinants and CNS dysfunction on ART adherence in PLWH. Hyp 2. Exposure to sexual/physical trauma or violence and/or impairments/decline in declarative memory, cognitive control, and NVS will adversely affect ART adherence. Exploratory Aim 3: Determine biomarkers that relate most strongly and reliably to CNS dysfunction in the context of HIV and/or psychosocial determinants. Hyp 3: Different biomarkers of neuronal damage and CNS inflammation will relate to patterns of impairment/decline in declarative memory, cognitive control, motor, and NVS in the context of HIV and/or exposure to sexual/physical trauma or violence. We will also build capacity to evaluate and conduct research in mental health disorders and introduce new measures of adherence to our cohort. Our proposal addresses several high priority research topics for the NIH Office of AIDS Research including HIV-associated comorbidities, basic research to understand the pathogenesis of mental health disorders in HIV infection, and research to identify viral reservoirs that could lead to a cure for HIV infection.