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

描述（由申请人提供）：撒哈拉以南非洲数百万艾滋病毒感染者现在接受挽救生命的抗逆转录病毒治疗（ART），但死亡率仍然很高。我们最近确定了吲哚2，3-双加氧酶-1（IDO）色氨酸催化途径-最近被认为是HIV发病机制的一个重要决定因素-作为这种情况下死亡率的一个强有力的预测因素。本提案的目标是描述抑制性ART对这一途径的长期影响，描述介导其与发病率和死亡率相关的免疫机制，并评估流行的合并感染对体内这一途径的贡献，以确定这种情况下新干预措施的目标。在乌干达的姆巴拉拉，对500多名艾滋病毒感染者进行了首次抗逆转录病毒疗法的研究，该研究计划在未来两年再招募250名参与者。在该队列的初步数据中，我们已经观察到吲哚2，3-双加氧酶（IDO）诱导的色氨酸catalytic炎症途径（ART前和早期病毒抑制期间）与随后的死亡率之间存在强烈的独立关系。然而，在长期ART介导的病毒抑制期间IDO诱导保持异常的程度、介导IDO诱导的色氨酸catalysts和发病率/死亡率之间的关系的特异性免疫机制以及包括肠道蠕虫、疟疾和CMV在内的普遍合并感染在体内促成该途径的程度仍不清楚。为了解决这些问题，我们将评估尽管进行了5年的抑制性抗逆转录病毒治疗，但与年龄、性别和县以下匹配的100名未感染HIV的乌干达人队列相比，该途径仍然异常的程度（目标1），IDO诱导的色氨酸catenorase与死亡率和结核病发病率之间相关的免疫学介质（目标2），以及慢性/复发性无症状合并感染（包括蠕虫、疟疾和CMV）对IDO诱导的色氨酸catalysis的影响（目的3）。这项研究将是第一个充分描述IDO途径对撒哈拉以南非洲启动抗逆转录病毒疗法的发病率和死亡率的贡献的研究，并将确定干预措施的具体目标，以进一步降低大多数艾滋病毒感染者生活的这一环境中的发病率和死亡率。

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.