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

项目摘要 神经认知障碍（NCI）影响高达50%的艾滋病毒感染者（PWH），包括 控制良好的感染。生理性别是PWH患者NCI的重要决定因素。最强 现有证据表明，全球范围内，感染艾滋病毒的妇女比感染艾滋病毒的男子有更大的认知缺陷 最重要的是，在学习、记忆和处理速度方面。尽管女性占了美国人口的一半， 尽管世界上的艾滋病毒感染者人数众多，但很少有研究关注艾滋病毒感染者性别差异的机制。 PWH中NCI的患病率和发病机制，尽管这些差异可能对 为女性和男性的NCI制定不同的治疗方法。 至少有两种途径可能会对艾滋病毒感染者的认知健康产生不同的影响， 与脑血管损伤的相关性：（1）心血管疾病（CVD）风险因素和（2）免疫 激活和炎症。我们的中心假设是，NCI在感染艾滋病毒的妇女中比在感染艾滋病毒的妇女中更普遍。 HIV男性患者由于更大的负担和脑血管损伤的进展， CVD危险因素和免疫激活的影响。在目标1中，我们将确定性别是否会改变 脑血管病危险因素和免疫激活与PWH脑血管损伤的关系在目标2中，我们 比较艾滋病毒感染者男女脑血管损伤的负担和进展。在目标3中， 我们将研究脑血管损伤在多大程度上介导了NCI的高患病率和下降， 如果性别改变脑血管损伤和NCI之间的关联， 为了实现我们的目标，我们提出了一项前瞻性研究，该研究将利用 美国国立卫生研究院资助的多中心艾滋病队列研究（MACS）/妇女机构间艾滋病研究（WIHS）合并 队列研究（MWCCS）。我们将入组150名女性（100名绝经后女性和50名绝经前女性） 和来自MWCCS的100名年龄匹配的男性，以确保研究有足够的把握度来确定性别 改变了CVD危险因素、免疫激活、脑血管损伤和NCI之间的关联。到 在MWCCS研究中收集的纵向神经心理学数据和储存的血液标本，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，这将产生一个完整的脑血管损伤的轮廓。我们还将测量 免疫激活和炎症标志物与脑血管损伤和NCI相关， PWH和已被证明是女性高于男性。这项研究的结果将提供 关于脑血管疾病的负担和进展以及 PWH中NCI的发病机制，这将为临床试验（包括目标研究）的合理设计提供信息 人口，在其中测试干预措施，以预防和治疗非传染性疾病的PWH。

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.