IDO-induced Tryptophan Catabolism and Mortality in Treated HIV-infected Africans

描述(申请人提供)：撒哈拉以南非洲的数百万艾滋病毒感染者现在正在接受挽救生命的抗逆转录病毒疗法(ART)，但死亡率仍然很高。我们最近发现吲哚2，3-双加氧酶-1(IDO)色氨酸分解代谢途径--最近被认为是HIV发病的一个重要决定因素--在这种情况下是一个强有力的死亡率预测因子。这项建议的目标是表征抑制性ART对这一途径的长期影响，表征其与发病率和死亡率之间的联系的免疫学机制，并评估体内普遍的联合感染对这一途径的贡献，确定在这一背景下进行新干预的目标。我们将在乌干达艾滋病农村治疗结果(UARTO)队列中解决这些问题，这是一项针对500多名HIV感染者的研究，该研究在乌干达姆巴拉拉开始他们的第一个ART方案，该研究计划在未来两年内再招募250名参与者。在这个队列的初步数据中，我们已经观察到吲哚2，3-双加氧酶(IDO)诱导的色氨酸分解代谢炎症途径(ART前和早期病毒抑制期间)的程度与随后的死亡率之间存在强烈的、独立的关系。然而，在ART介导的长期病毒抑制过程中，IDO诱导的异常程度仍不清楚，IDO诱导的色氨酸分解代谢与发病率/死亡率关系的特定免疫学机制，以及体内流行的混合感染，包括肠道蠕虫、疟疾和CMV对这一途径的贡献程度仍不清楚。为了解决这些问题，我们将评估尽管进行了5年抑制性抗逆转录病毒治疗，但这一途径仍然异常的程度，与100名未感染艾滋病毒的乌干达人的年龄、性别和县以下匹配的队列相比(目标1)，IDO诱导的色氨酸分解代谢与死亡率和发病率结核病之间关系的免疫学介质(目标2)，以及包括蠕虫、疟疾和CMV在内的慢性/反复无症状混合感染对IDO诱导的色氨酸分解代谢的影响(目标3)。这项研究将首次全面描述IDO途径对发起抗逆转录病毒疗法的撒哈拉以南非洲人的发病率和死亡率的贡献，并将确定干预措施的具体目标，以进一步降低这一环境中的发病率和死亡率，因为大多数艾滋病毒感染者生活在那里。

DESCRIPTION (provided by applicant): Millions of HIV-infected individuals in sub-Saharan Africa now receive life-saving antiretroviral therapy (ART), but mortality remains high. We have recently identified the indole 2,3-dioxygenase-1 (IDO) tryptophan catabolism pathway - which has recently been implicated as an important determinant of HIV pathogenesis - as a strong predictor of mortality in this setting. The goal of this proposal is to characterize the long-term impact of suppressive ART on this pathway, to characterize the immunologic mechanisms that mediate its association with morbidity and mortality, and to assess the contributions of prevalent co-infections to this pathway in vivo, to identify targets for novel interventions in this setting.We will address these issues in the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort, a study of over 500 HIV-infected individuals initiating their first ART regimen in Mbarara, Uganda, which plans to enroll an additional 250 participants over the next 2 years. In preliminary data from this cohort, we have already observed a strong, independent relationship between the extent of indole 2,3-dioxygenase (IDO)-induced tryptophan catabolism inflammatory pathway (both pre-ART and during early viral suppression) and subsequent mortality. However, the degree to which IDO induction remains abnormal during long-term ART- mediated viral suppression, the specific immunologic mechanisms mediating the relationship between IDO- induced tryptophan catabolism and morbidity/mortality, and the degree to which prevalent co-infections including intestinal helminthes, malaria, and CMV contribute to this pathway in vivo remain unclear. To address these issues, we will assess the degree to which this pathway remains abnormal despite 5 years of suppressive antiretroviral therapy compared to a cohort of age-, gender-, and sub-county-matched cohort of 100 HIV-uninfected Ugandans (Aim 1), the immunologic mediators of the association between IDO-induced tryptophan catabolism and both mortality and incident TB (Aim 2), and the impact of chronic/recurrent asymptomatic co-infections including helminthes, malaria, and CMV on IDO-induced tryptophan catabolism (Aim 3). This study will be the first to fully characterize the contribution of the IDO pathway to morbidity and mortality in sub-Saharan Africans initiating ART and will identify specific targets for interventions to further decrease morbidity and mortality in this setting, where the majority o HIV-infected individuals live.