Coronary Atherosclerosis and Immune Activation in HIV and Tuberculosis Infection

项目摘要 艾滋病毒携带者(PLWH)患心血管疾病(CVD)的风险比 对普通民众来说。免疫激活，特别是由混合感染驱动的，被认为是一个重要的 风险增加的贡献者。然而，结核分枝杆菌(Mtb)合并感染是否增加 PLWH的心血管疾病风险尚不清楚。潜在结核病感染(LTBI)影响着世界四分之一的人口， 在艾滋病毒流行地区，重叠感染率高达50%。我们的初步数据指向一个重要的 LTBI在增加心血管疾病风险中的作用。在未感染艾滋病毒的人中，我们已经证明了LTBI是 与急性心肌梗死的可能性增加和梗阻发生率增加有关 冠状动脉疾病，独立于传统的心血管疾病危险因素。在概念验证小鼠实验中， 我们发现，持续的、无症状的分枝杆菌感染加剧了主动脉斑块的发展， 而这种斑块负荷与单核细胞数量的变化直接相关。我们的总体假设是 在PLWH中，LTBI合并感染通过以下途径促进动脉粥样硬化性心血管疾病(ASCVD)的发展 增强免疫活性和促炎刺激，导致斑块负担增加和不稳定。 在这个项目中，我们将在结核病流行地区秘鲁利马研究有无LTBI的PLWH。在这个目标1中 建议，我们将定义PLWH中阻塞性冠状动脉疾病和斑块易损性的负担 使用先进的冠状动脉CT血管成像研究的LTBI。在目标2中，我们将确定 LTBI和LTBI治疗如何影响单核细胞和Mtb的激活、功能和代谢 应用高维多参数流式细胞术对PLWH中特异性T细胞的深入研究 纵向免疫细胞图谱。最后，我们将研究免疫变异之间的关系 2年内冠状动脉斑块体积的活化标志物和变化。成功完成了 拟议的研究目标将定义LTBI作为ASCVD风险的贡献者和免疫激活在 PLWH。我们的结果将为有针对性的机制研究和干预试验奠定基础，旨在安全地 减少LTBI后PLWH的潜在免疫激活，并强调LTBI控制作为一种 降低ASCVD风险的治疗策略。此外，所获得的知识将进一步增强我们更广泛的 对ASCVD的机制认识。

Project Summary Persons living with HIV (PLWH) have a 1.5- to 2-fold increased risk of cardiovascular disease (CVD) compared to the general population. Immune activation, particularly driven by coinfections, is considered an important contributor in that enhanced risk. However, whether Mycobacterium tuberculosis (Mtb) coinfection increases CVD risk in PLWH is unknown. Latent tuberculosis infection (LTBI) affects a quarter of the world population, with coinfection rates as high as 50% in HIV-endemic areas. Our preliminary data point towards an important role of LTBI in augmenting CVD risk. In HIV-uninfected individuals, we have demonstrated that LTBI is associated with increased likelihood of acute myocardial infarction and higher prevalence of obstructive coronary artery disease, independent of traditional CVD risk factors. In proof-of-concept mouse experiments, we revealed that persistent, asymptomatic mycobacterial infection exacerbated aortic plaque development, and that plaque burden directly correlated with alterations of monocyte populations. Our overall hypothesis is that in PLWH, LTBI coinfection contributes to the development of atherosclerotic CVD (ASCVD) through enhanced immune activation and pro-inflammatory stimuli resulting in increased plaque burden and instability. In this project, we will study PLWH with and without LTBI in Lima, Peru, a TB-endemic area. In Aim 1 of this proposal, we will define the burden of obstructive coronary artery disease and plaque vulnerability in PLWH with LTBI using advanced coronary computed tomography angiography studies. In Aim 2, we will determine how LTBI and LTBI treatment affects the activation, function, and metabolic profile of monocytes and Mtb- specific T cells in PLWH, using high-dimensional multi-parameter spectral flow cytometry for in-depth longitudinal immune cell profiling. Finally, we will study the relationship between variations on immune activation markers and changes on coronary plaque volume over 2 years. Successful accomplishment of the proposed research aims will define the role of LTBI as a contributor of ASCVD risk and immune activation in PLWH. Our results will set the stage for targeted mechanistic studies and interventional trials aimed at safely reducing underlying immune activation in PLWH with LTBI, and emphasize the importance of LTBI control as a therapeutic strategy to mitigate ASCVD risk. Moreover, the knowledge gained will further enhance our broader mechanistic understanding of ASCVD.