Altered mitochondrial function and HIV-associatedcardiometabolic disease in populations from South Africa and Kenya (MITO-SAKen)

项目总结 目前的证据表明，撒哈拉以南非洲地区正面临着双重疾病负担，艾滋病毒和心脏病-- 新陈代谢疾病似乎正在发生碰撞。心脏瓣膜的负担越来越重，更是雪上加霜。 可归因于艾滋病毒的博莱氏病，这将进一步影响该区域本已艰难的公共卫生资源。 相对缺乏关于艾滋病毒和心脏瓣膜病变之间的交叉的流行病学和机械学研究- 因此，撒哈拉以南非洲人口中的博莱氏病是一个重大的知识差距。有几个因素， 包括线粒体功能障碍在内，参与了HIV相关心脏代谢紊乱的发病机制。 放松点。线粒体功能障碍与HIV和心脏代谢性疾病有关，之前的研究 已经证明线粒体参与了几种与心脏代谢相关的疾病 艾滋病毒携带者(PLWH)。虽然HIV相关心脏代谢性疾病的一个共同的潜在机制仍然存在 难以捉摸的线粒体功能障碍可能独特地将心脏代谢性疾病的发病机制推向更大的 与没有感染艾滋病毒的人相比，感染艾滋病毒的人的感染程度更高。撒哈拉以南非洲的PLWH特别容易受到MIJ的影响。 由于内在和外在危险因素的独特汇聚导致的软骨功能障碍，包括暴露于 地方性病原体和高度炎症。在这项研究中，假设抗逆转录病毒疗法 (ART)-撒哈拉以南非洲地区患有心脏代谢性疾病的有经验的PLWH将显示更大的线粒体 与没有心脏代谢性疾病的PLWH和没有HIV的对照组相比，功能障碍。这一假说将 将在一项由南非和肯尼亚队列组成的探索性横断面研究中进行测试。以特定的目标 1、线粒体呼吸功能(用最先进的高分辨率呼吸测量法和荧光法测量 技术)将在感染和不感染艾滋病毒的参与者中进行比较，并将确定丝裂原是否- 在伴有心脏代谢性疾病的PLWH患者中，干功能障碍更为明显。在特定目标2中，信使核糖核酸表达 与线粒体功能和动力学相关的基因Sion将在有和没有参加的参与者中进行比较 HIV，并将确定心脏代谢性疾病的PLWH是否有不同的基因表达。重新- 最新的病理生理过程，包括炎症、免疫和内分泌，将被测量到 补充AIMS 1和2中的线粒体功能和基因表达实验。 将提供初步证据，表明伴有心脏节律的PLWH患者存在高度的线粒体功能障碍- 来自南非和肯尼亚的代谢性疾病。这些结果可能有利于该区域的公共卫生，包括 筛查有线粒体功能障碍风险的PLWH，修订一线ART，包括含有有丝分裂素的药物 线粒体毒性，以及PLWH对心脏代谢性疾病的更大重视。韩国新的研究网络 非洲、肯尼亚和美国将被打造成具有强大能力发展重点的地区。

PROJECT SUMMARY Current evidence suggests that sub-Saharan Africa is facing a double burden of disease, with HIV and cardi- ometabolic disease seemingly on a collision course. This is compounded by the growing burden of cardiometa- bolic disease attributable to HIV, which will further impact already struggling public health resources in the region. The relative lack of epidemiological and mechanistic studies on the intersection between HIV and cardiometa- bolic disease in sub-Saharan African populations therefore represents a major knowledge gap. Several factors, including mitochondrial dysfunction, are implicated in the pathogenesis of HIV-associated cardiometabolic dis- ease. Mitochondrial dysfunction has been linked to both HIV and cardiometabolic disease and previous studies have demonstrated mitochondrial involvement in several cardiometabolic-related pathologies in people living with HIV (PLWH). Whilst a common underlying mechanism of HIV-associated cardiometabolic disease remains elusive, mitochondrial dysfunction may uniquely drive the pathogenesis of cardiometabolic disease to a greater extent in people with compared to without HIV. PLWH in sub-Saharan Africa are particularly susceptible to mi- tochondrial dysfunction due to a unique convergence of intrinsic and extrinsic risk factors, including exposure to endemic pathogens and high levels of inflammation. In this study, it is hypothesized that antiretroviral therapy (ART)-experienced PLWH with cardiometabolic disease in sub-Saharan Africa will show greater mitochondrial dysfunction compared to PLWH without cardiometabolic disease and controls without HIV. The hypothesis will be tested in an exploratory, cross-sectional study comprising cohorts in South Africa and Kenya. In Specific Aim 1, mitochondrial respiratory function (measured by state-of-the-art high resolution respirometry and fluorometry technology) will be compared in participants with and without HIV, and it will be determined whether mitochon- drial dysfunction is more pronounced in PLWH with cardiometabolic disease. In Specific Aim 2, mRNA expres- sion of genes linked to mitochondrial function and dynamics will be compared in participants with and without HIV, and it will be determined whether gene expression is different in PLWH with cardiometabolic disease. Re- lated pathophysiological processes, including inflammatory, immunological and endocrine, will be measured to complement the mitochondrial function and gene expression experiments in Aims 1 and 2. This exploratory study will provide preliminary evidence that heightened mitochondrial dysfunction is present in PLWH with cardiomet- abolic disease from South Africa and Kenya. These results may benefit public health in the region, including screening of PLWH at risk of mitochondrial dysfunction, revision of 1st line ART that includes drugs with mito- chondrial toxicity, and stronger emphasis on cardiometabolic disease in PLWH. New research networks in South Africa, Kenya and the US will be forged, with a strong capacity development focus.