Immune Reconstitution Inflammatory Syndrome in HIV-TB infected patients in Peru

由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（TB）感染全世界近三分之一的人，超过1100万人同时感染HIV和Mtb。结核病仍然是全世界艾滋病毒患者死亡的主要原因。艾滋病患者中与结核病相关的大多数发病率是由于免疫缺陷导致的不受控制的感染。然而，随着有效的抗逆转录病毒疗法的出现，人们认识到了新的综合征，这些综合征被认为是免疫重建期间的炎症反应所致。这些综合征称为免疫重建炎症综合征（IRIS），在开始有效抗逆转录病毒治疗的活动性结核病患者中约有30%发生。IRIS的免疫发病机制知之甚少，但似乎涉及对微生物抗原过度旺盛的免疫/炎症反应。CD 4 T细胞的一个子集，称为T调节（Treg）细胞，已被公认参与调节T细胞和炎症反应。T细胞最初通过其CD 4和CD 25（IL 2受体α链）的表达来识别，这些标志物也与活化的T细胞共享。最近，发现TcB独特地表达转录因子Foxp 3。在先前的研究中，我们已经证明了TcB和HIV之间的复杂关系。Foxp 3 + T细胞总数减少与总CD 4+细胞数减少平行。然而，Foxp 3阳性的CD 4细胞比例在晚期疾病中是可变的。此外，IRIS主要发生在Foxp 3+细胞比例低的人中。该提议的广泛假设是，Treg数量和功能在HIV-Mtb共感染患者中被抑制，并且Treg缺陷使共感染患者易患慢性免疫激活和IRIS。当前提议将通过前瞻性研究开始抗逆转录病毒疗法的HIV-TB共感染患者的队列来确定Treg细胞在IRIS的免疫发病机制中的作用。具体目的是检验出现IRIS的HIV-TB患者在开始抗逆转录病毒治疗之前调节性T细胞比例降低的假设（aim 1），比较出现IRIS和未出现IRIS的AIDS结核病患者的免疫遗传学（aim 2），检验TB患者的IRIS与对TB肽的过度抗原驱动应答相关的假设（aim 3），和TB特异性Treg功能在有或没有IRIS的患者中重建TB肽特异性调节细胞应答（目的4）。为了实现这些目标，我们组建了一个由来自德克萨斯州的有成就的研究人员和来自秘鲁利马的有经验的临床研究人员组成的团队，大量艾滋病毒-结核病合并感染患者现在开始接受抗逆转录病毒治疗。这些研究应阐明易患IRIS的免疫调节异常，这是一个新出现的问题，并为结核病流行地区优化抗逆转录病毒治疗提供更好的科学依据。在结核病常见的地区，免疫重建炎症综合征使艾滋病的治疗变得非常复杂。这项研究将确定这种综合征的遗传和免疫危险因素。这些信息对于改善发展中国家和美国大量两种感染者的治疗非常重要。

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infects nearly 1 in 3 people in the world with over 11 million people co-infected with HIV and Mtb. TB remains the major cause of death in HIV patients worldwide. Most morbidity associated with TB in HIV patients is due to uncontrolled infection as a result of immunodeficiency. As effective anti-retroviral therapy has become available, however, new syndromes have been recognized, which are thought to result from an inflammatory response during immune reconstitution. These syndromes, termed Immune Reconstitution Inflammatory Syndrome (IRIS), develop in about 30% of active TB patients beginning effective antiretroviral therapy. The immunopathogenesis of IRIS is poorly understood, but seems to involve an overly exuberant immune/inflammatory response to microbial antigens. A subset of CD4 T cells, termed T regulatory (Treg) cells, has been recognized that are involved in modulating T cell and inflammatory responses. Tregs were initially recognized by their expression of CD4 and CD25 (the IL2 receptor alpha chain), markers also shared with activated T cells. More recently, Tregs were found to uniquely express the transcription factor Foxp3. In prior studies, we have demonstrated a complex relationship between Tregs and HIV. There was a decrease in total number of Foxp3+ Tregs in parallel to the decrease in total CD4+ cell numbers. However, the proportion of CD4 cells positive for Foxp3 was variable in advanced disease. Furthermore, IRIS develops mainly in those with low proportions of Foxp3+ cells. The broad hypothesis for this proposal is that Treg number and function are depressed in HIV-Mtb co-infected patients and that Treg defects predispose co-infected patients to chronic immune activation and IRIS, The current proposal will determine the role of Treg cells in the immunopathogenesis of IRIS by prospectively studying a cohort of HIV-TB co-infected patients beginning antiretroviral therapy. The specific aims are to test the hypothesis that HIV-TB patients who develop IRIS have a decrease of regulatory T cell proportions prior to starting antiretroviral therapy (aim1), to compare the immunogenetics of AIDS patients with tuberculosis who do and do not develop IRIS (aim 2), to test the hypothesis that IRIS in TB patients is associated with an exaggerated antigen-driven response to TB peptides (aim 3), and to TB-specific Treg function in patients with or without IRIS reconstitute a TB peptide-specific regulatory cell response (aim 4). To accomplish these goals, we have assembled a team of accomplished investigators from Texas and experienced clinician-investigators from Lima, Peru, with a large population of HIV-TB co-infected patients now beginning antiretroviral therapy. These studies should elucidate abnormalities in immunoregulation that predispose to IRIS, a problem emerging and provide a better scientific basis for optimizing antiretroviral therapy in TB endemic areas. PUBLIC HEALTH RELEVANCE Immune reconstitution inflammatory syndrome significantly complicated treatment of AIDS in areas where tuberculosis is common. This study will identify genetic and immune risk factors for this syndrome. The information will be important for improving treatment for the large number of people with both infections in developing countries, as well as in the United States.