Sex differences in the contribution of cerebrovascular injury and immune activation to neurocognitive impairment in HIV infection

项目总结 神经认知障碍(NCI)影响高达50%的艾滋病毒携带者(PWH)，包括患有 感染控制得很好。生物学性别是PWH患者NCI的重要决定因素。最强的 现有证据表明，在全球范围内，携带艾滋病毒的女性比携带艾滋病毒的男性存在更大的认知缺陷 最突出的是，在学习、记忆和处理速度方面。尽管女性占了女性总数的一半 对于世界上艾滋病病毒感染者来说，很少有研究集中在性别差异背后的机制。 PWH中NCI的患病率和发病机制，尽管这些差异可能对 为女性和男性开发不同的NCI治疗方法。 至少有两条途径可能对艾滋病毒携带者和男性的认知健康产生不同的影响，两者都是通过他们的 与脑血管损伤的关系：(1)心血管疾病(CVD)危险因素和(2)免疫 激活和发炎。我们的中心假设是NCI在感染艾滋病毒的妇女中比在 男性艾滋病毒携带者由于负担较大而脑血管损伤的进展增加了对 心血管疾病危险因素与免疫激活的关系。在目标1中，我们将确定性别是否会改变 脑血管疾病危险因素及免疫激活与重型肝炎脑血管损伤的关系在目标2中，我们将 比较女性和男性HIV感染者脑血管损伤的负担和进展。在《目标3》中， 我们将检查脑血管损伤在多大程度上调节NCI的较高患病率并下降 在感染艾滋病毒的妇女中，如果性别改变了脑血管损伤和非脑血管病变之间的联系。 为了达到我们的目标，我们提出了一项前瞻性研究，将利用 NIH资助的多中心艾滋病队列研究(MACS)/妇女机构间艾滋病毒研究(WIHS)合并 队列研究(MWCCS)。我们将招收150名妇女(100名绝经后和50名绝经前妇女) 以及来自MWCCS的100名年龄匹配的男性，以确保这项研究有足够的力量来确定性别 修改CVD危险因素、免疫激活、脑血管损伤和NCI之间的关系。至 在MWCCS研究中收集的纵向神经心理数据和储存的血液样本，我们将 增加全面的脑血管成像评估，包括脑血管反应性，大动脉， 和小血管疾病，这将导致脑血管损伤的完整轮廓。我们还将衡量 免疫激活和炎症标志物与脑血管损伤和非脑血管病变的关系 与男性相比，女性的PWH和PWH更高。这项研究的结果将提供 关于脑血管疾病负担和进展的性别差异的新信息 PWH中NCI的发病机制，这将为临床试验的合理设计提供信息，包括靶向研究 对威尔斯亲王医院中预防和治疗NCI的干预措施进行测试。

PROJECT SUMMARY Neurocognitive impairment (NCI) affects up to 50% of persons living with HIV (PWH), including individuals with well-controlled infection. Biological sex is an important determinant of NCI among PWH. The strongest available evidence indicates that women with HIV have greater cognitive deficits globally than men with HIV and, most prominently, in learning, memory, and processing speed. Although women make up half of the world’s HIV population, few studies have focused on the mechanisms underlying sex differences in the prevalence and pathogenesis of NCI in PWH, despite the consequences that these differences could have on developing distinct therapeutic approaches to NCI for women and men. At least two pathways may differentially impact cognitive health in women and men with HIV, both through their association with cerebrovascular injury: (1) cardiovascular disease (CVD) risk factors and (2) immune activation and inflammation. Our central hypothesis is that NCI is more prevalent in women with HIV than in men with HIV due to greater burden and progression of cerebrovascular injury from increased susceptibility to the effects of CVD risk factors and immune activation. In Aim 1, we will determine if sex modifies the association of CVD risk factors and immune activation with cerebrovascular injury in PWH. In Aim 2, we will compare the burden and progression of cerebrovascular injury between women and men with HIV. In Aim 3, we will examine the extent to which cerebrovascular injury mediates the higher prevalence of NCI and decline in women with HIV and if sex modifies the association between cerebrovascular injury and NCI. To achieve our aims, we propose a prospective study that will leverage the research platform provided by the NIH-funded Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS). We will enroll 150 women (100 post-menopausal and 50 pre-menopausal women) and 100 age-matched men from the MWCCS to ensure the study is adequately powered to determine if sex modifies the associations between CVD risk factors, immune activation, cerebrovascular injury, and NCI. To the longitudinal neuropsychological data and stored blood specimens collected in the MWCCS study, we will add a comprehensive cerebrovascular imaging assessment, including of cerebral vasoreactivity, large artery, and small vessel disease, that will yield a complete profile of cerebrovascular injury. We will also measure immune activation and inflammatory markers that are associated with both cerebrovascular injury and NCI in PWH and have been shown to be higher in women compared with men. The findings of this study will provide new information on sex differences in the burden and progression of cerebrovascular disease and in the pathogenesis of NCI in PWH, which will inform the rational design of clinical trials, including the target study population, in which to test interventions to prevent and treat NCI in PWH.