The Contribution of Sleep and Circadian Disruption to Kynurenine Pathway Activation and Cardiometabolic Risk in Women with HIV

摘要 尽管对艾滋病毒进行了联合抗逆转录病毒治疗(CART)，但免疫激活和炎症仍然存在。这 慢性炎症会增加艾滋病毒相关心脏代谢的发病率和死亡率。我们的团队 最近发现一种特殊的分子机制-色氨酸-犬尿氨酸(Trp-Kyn)途径-是 在艾滋病毒中被破坏，并与动脉粥样硬化的进展有关。Trp-Kyn通路具有潜在的应用前景 在HIV和睡眠/昼夜节律调节中的重要性，因为HIV Tat蛋白和炎症分子 诱导Trp-kyn途径激活，导致Trp的降解，失衡和积聚 KYN及其下游代谢物，以及褪黑激素的减少，褪黑素是一种昼夜节律调节器，具有抗 炎性物质。睡眠和昼夜节律紊乱在艾滋病毒中非常普遍，睡眠和昼夜节律 众所周知，破坏会增加炎症。因此，睡眠和昼夜节律的紊乱可能会进一步 激活Trp-Kyn途径，增加艾滋病毒相关的心脏代谢性疾病的风险。这样做的目的是 应用是研究Trp-kyn通路作为睡眠和昼夜节律的分子机制。 中断会增加艾滋病毒相关心脏代谢性疾病的风险。我们还将调查互惠关系 HIV相关Trp-kyn通路激活可能反馈增加睡眠和昼夜节律的关系 颠覆。我们的多学科团队将利用正在进行的多地点妇女机构间艾滋病毒研究 (WIHS)特征良好的艾滋病毒+和人口结构相似的艾滋病毒妇女队列，具有广泛的 心脏代谢数据。我们来自WIHS的试点数据表明：(1)睡眠和昼夜节律紊乱在 WIHS队列，(2)睡眠和昼夜节律紊乱可以增强免疫激活，特别是在艾滋病毒- (3)Trp-Kyn通路激活会增加患心脏代谢性疾病的风险。因此，我们 将对240名女性(120名艾滋病病毒携带者，120名艾滋病病毒携带者，40-70岁)进行纵向研究设计，评估睡眠 和昼夜节律紊乱、Trp-Kyn通路激活和心脏代谢风险每年超过2年(3次 点)。目标1是确定睡眠和昼夜节律紊乱与睡眠和昼夜节律紊乱相关的程度，以及 预测，HIV+女性中Trp-Kyn通路的激活。目标2是确定睡眠和睡眠的程度 昼夜节律紊乱与艾滋病毒相关的心脏代谢性疾病风险相关，并可以预测。目标3 目的是确定Trp-kyn通路是否是一种将睡眠和昼夜节律紊乱与 艾滋病毒相关的心脏代谢性疾病风险增加。到目前为止，还没有研究过Trp-Kyn通路 作为睡眠/昼夜节律紊乱与HIV相关共病的机制的激活及其代谢产物 比如心脏代谢性疾病。这些结果将为我们提供新的见解，了解 睡眠和昼夜节律紊乱、Trp-Kyn通路激活与HIV相关的心脏代谢性疾病风险 并提供了一个坚实的基础，在此基础上测试有针对性的睡眠和昼夜节律干预，以降低患上 艾滋病毒携带者的心脏代谢性疾病。

ABSTRACT Immune activation and inflammation persist despite combination antiretroviral therapy (cART) for HIV. This chronic inflammation contributes to greater HIV-associated cardiometabolic morbidity and mortality. Our group recently found that a specific molecular mechanism - the tryptophan-kynurenine (TRP-KYN) pathway - is disrupted in HIV and associated with atherosclerosis progression. The TRP-KYN pathway is of potential importance in both HIV and sleep/circadian regulation because HIV Tat protein and inflammatory molecules induce TRP-KYN pathway activation, which results in a degradation of TRP, an imbalance and accumulation of KYN and its downstream metabolites, and a reduction in melatonin, which is a circadian regulator with anti- inflammatory properties. Sleep and circadian disruption are highly prevalent in HIV, and sleep and circadian disruption are well-recognized to increase inflammation. Therefore, sleep and circadian disruption may further activate the TRP-KYN pathway, increasing HIV-associated cardiometabolic disease risk. The objective of this application is to investigate the TRP-KYN pathway as a molecular mechanism by which sleep and circadian disruption increase risk for HIV-associated cardiometabolic disease. We will also investigate the reciprocal relationship by which HIV-related TRP-KYN pathway activation may feed back to increase sleep and circadian disruption. Our multidisciplinary team will leverage the ongoing multi-site Women's Interagency HIV Study (WIHS) cohort of well-characterized HIV+ and demographically similar HIV- women, which has extensive cardiometabolic data. Our pilot data from WIHS indicate that (1) sleep and circadian disruption is prevalent in the WIHS cohort, (2) sleep and circadian disruption can potentiate immune activation, particularly in HIV- infected individuals, and (3) TRP-KYN pathway activation increases risk for cardiometabolic disease. Thus, we will study 240 women (120 HIV+ aviremic, 120 HIV-, 40-70 y) in a longitudinal study design, assessing sleep and circadian disruption, TRP-KYN pathway activation and cardiometabolic risk yearly over 2 years (3 time points). Aim 1 is to determine the degree to which sleep and circadian disruption are associated with, and can predict, TRP-KYN pathway activation in HIV+ women. Aim 2 is to determine the degree to which sleep and circadian disruption are associated with, and can predict, HIV-associated cardiometabolic disease risk. Aim 3 is to determine whether the TRP-KYN pathway is a mechanism that links sleep and circadian disruption to an increase in HIV-associated cardiometabolic disease risk. No studies to date have examined TRP-KYN pathway activation and its metabolites as a mechanism linking sleep/circadian disruption to HIV-related comorbidities such as cardiometabolic disease. Results will provide novel insights into the mechanistic relationships between sleep and circadian disruption, TRP-KYN pathway activation, and HIV-associated cardiometabolic disease risk and provide a strong foundation upon which to test targeted sleep and circadian interventions to reduce risk for cardiometabolic disease in women with HIV.