Humanized mice as a model to study the role of oxidized lipids in HIV-related cardiovascular disease

项目摘要/摘要 心血管疾病(CVD)正成为HIV-1感染者死亡的主要原因。这个 HIV-1感染、心血管疾病和与HIV感染相关的免疫系统激活之间的联系机制 (免疫激活)仍不清楚。尽管有有效的抗逆转录病毒疗法(ART)，但仍有持久的免疫。 与CVD进展相关的激活。越来越清楚的是，激活的标志物 单核/巨噬细胞(M/M)的数量可能比T细胞参数更准确地预测发病率和死亡率 接受过艺术治疗的个体。M/M与氧化脂质(OxPLs)在动脉和肠道等组织中共定位， HIV-1感染的最大蓄水池之一，体内大部分M/M都在这里。 提示肠道氧化脂质的形成可能对炎症和CVD有调节作用。M/M还与 氧化脂蛋白和处于HIV-1感染、肠道相关和全身感染之间的交叉点 炎症、心血管疾病和免疫激活。解开氧化脂质对M/M、心血管疾病和HIV-1的影响 发病机制可能有助于开发新的治疗方法来管理艾滋病毒相关的心血管疾病。这样的疗法 包括高密度脂蛋白(高密度脂蛋白)模拟肽，其模拟高密度脂蛋白正常功能 氧磷脂和抗炎特性。我们假设HIV-1和氧化的脂类形成了一个恶性循环 HIV-1增强的M/M激活和炎症是导致HIV-1感染者心血管疾病的原因之一。整体而言 目的是探索HIV-1感染是否导致氧化脂质和促炎/ 导致动脉粥样硬化的M/M，尽管ART有效。这个项目有两个目标。目标1将在一个 人源化小鼠体内模型HIV-1，尽管ART有效，但直接诱导氧化形成 被高密度脂蛋白模拟物削弱的脂类。Aim 2将使用相同的小鼠模型在体内确定是否有高密度脂蛋白 模拟物改善慢性粒细胞间充质干细胞的促氧化、促炎、活化和致动脉粥样硬化表型 治疗HIV-1感染。鉴于接受抗逆转录病毒治疗的HIV-1感染者可能会继续出现M/M升高 激活和氧化脂质，这样的方法可以减少剩余的额外发病率和死亡率 尽管。这项工作具有创新性，对公共卫生有影响，并直接涉及研究优先事项 关于艾滋病毒相关的合并症。

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is becoming a major cause of death in persons with HIV-1 infection. The mechanisms that link HIV-1 infection, CVD and activation of the immune system associated with HIV infection (immune activation) remain unknown. Despite effective antiretroviral therapy (ART) there is persistent immune activation that is associated with CVD progression. It is becoming increasingly clear that markers of activation of monocyte/macrophages (M/M) may more accurately predict morbidity and mortality than T-cell parameters in ART-treated individuals. M/M co-localize with oxidized lipids (oxPLs) in tissues such as arteries and the gut, one of the largest reservoirs in HIV-1 infection that harbors most of the body's M/M. Emerging evidence suggests that formation of oxidized lipids in gut may regulate inflammation and CVD. M/M also interact with oxidized lipoproteins and are at the intersection between HIV-1 infection, gut related and systemic inflammation, CVD and immune activation. Unraveling how oxidized lipids affect M/M, CVD and HIV-1 pathogenesis may contribute to development of new therapies to manage HIV-related CVD. Such therapies include High Density Lipoprotein (HDL) mimetic peptides that mimic normal functions of HDL such as binding of oxPLs and anti-inflammatory properties. We hypothesize that HIV-1 and oxidized lipids foster a vicious cycle of HIV-1-enhanced M/M activation and inflammation that drive CVD in HIV-1 infected individuals. The overall goal is to explore whether HIV-1 infection drives increased formation of oxidized lipids and proinflammatory/ proatherogenic M/M despite effective ART. This project is organized into two aims. Aim 1 will explore in a humanized mouse model in vivo whether HIV-1, despite effective ART, directly induces formation of oxidized lipids that is attenuated by HDL mimetics. Aim 2 will determine in vivo using the same mouse model if HDL mimetics improve prooxidant, proinflammatory, activated and proatherogenic phenotype of M/M in chronic treated HIV-1 infection. Given that HIV-1-infected persons on ART may continue to have elevated M/M activation and oxidized lipids, such an approach could reduce the excess morbidity and mortality remaining despite. This work is innovative, has an impact on public health and directly addresses research priorities regarding HIV-associated comorbidities.