Dissecting the pathogenesis of HIV-TB Immune reconstitution inflammatory syndrome

尽管全球卫生保健取得了重大进展，但估计仍有150万人死亡， 2018年结核病（TB）近100万艾滋病毒感染者患上了结核病。共- 感染艾滋病毒和结核病与高发病率和死亡率以及结核病药物和抗结核药物治疗有关， 逆转录病毒疗法现已普遍提供。抗逆转录病毒疗法后的结核病药物治疗可长期改善 艾滋病毒感染者的免疫系统受到严重抑制。迹象 并且疾病症状在治疗开始后很快改善，但是在许多情况下，疾病可以复发， 随着免疫系统从抗逆转录病毒治疗中重新建立，临床表现更差。这被称为结核病- 相关的免疫重建炎症综合征（TB-IRIS），在患者中更常见 在治疗前免疫系统受到严重抑制的人，以及那些在治疗前 开始TB治疗和ART。关于TB-IRIS如何或为什么发生以及如何最好地治疗 我们假设TB-IRIS的症状是由以下因素之间的动态相互作用驱动的： 免疫系统，结核分枝杆菌（Mtb，导致结核病的细菌）和艾滋病毒深入内部 体内受感染的组织，如肺肉芽肿。事实上，我们对在地球上发生的事情一无所知。 结核分枝杆菌和艾滋病毒在TB-IRIS期间相互作用的组织。该提案将开发结核病的动物模型- IRIS通过利用我们预先存在的HIV-TB共感染模型， 感染者像人类一样接受结核病药物治疗和抗逆转录病毒疗法。我们将使用先进的成像技术， 免疫学和微生物学工具，以更好地了解如何和为什么TB-IRIS发展，以及哪些因素可以 预测它的出现。目标1将确定在该模型中TB-IRIS发生的频率以及Mtb和 SIV在治疗过程中仍然存在于组织中。我们还将详细检查 发生在组织中，但特别是肺（肉芽肿）和淋巴结，通过一系列体内图像， 更好地了解导致TB-IRIS的事件及其预测因素。在目标2中，我们将执行详细的 检测TB-IRIS期间组织和血液中的免疫学事件。组织特异性（肺 肉芽肿和淋巴结）的免疫应答将与Mtb细菌和病毒的量相关 结合影像学检查结果，以便我们更好地了解TB-IRIS的病因。我们的短期目标是 更好地了解TB-IRIS的发病机制，这些发现将最终导致更好的 治疗和预防TB-IRIS是我们的长期目标。

Despite major advances in global health care, there were an estimated 1.5 millions deaths and 10 million new cases of tuberculosis (TB) in 2018. Nearly 1 million people living with HIV developed tuberculosis (TB). Co- infection with HIV and TB is associated with high morbidity and mortality and treatment with TB drugs and anti- retroviral (ART) therapy is now universally available. TB drug treatment followed by ART improves long term survival, particularly among those whose immune systems are severely suppressed from HIV infection. Signs and symptoms of disease improve soon after treatment is started but, in many cases, disease can recur and appear clinically worse as the immune system is being re-established from ART. This is known as TB- associated Immune Reconstitution Inflammatory Syndrome (TB-IRIS) and is more common among patients with severely suppressed immune systems before treatment and those who have a short time interval between starting TB treatment and ART. Very little is known about how or why TB-IRIS occurs and how to best to treat or even prevent it. We hypothesize that symptoms of TB-IRIS are driven by the dynamic interaction between the immune system, Mycobacterium tuberculosis (Mtb, the bacteria that causes TB) and HIV deep within infected tissues in the body such as the lung granuloma. Virtually nothing is known about what happens in the tissues where both Mtb and HIV interact during TB-IRIS. This proposal will develop an animal model of TB- IRIS by taking advantage of our pre-existing model of HIV-TB co-infection in which animals with SIV-Mtb co- infection undergo TB drug treatment and ART just like humans. We will use sophisticated imaging, immunology and microbiologic tools to better understand how and why TB-IRIS develops and what factors can predict its emergence. Aim 1 will determine how often TB-IRIS occurs in this model and to what extent Mtb and SIV remain in the tissues during treatment. We will also perform a detailed examination of the changes that occur in the tissues but especially the lungs (granulomas) and lymph nodes through serial in vivo images to better understand the events that lead to TB-IRIS and its predictors. In Aim 2, we will perform a detailed examination of the immunologic events in the tissues and blood during TB-IRIS. Tissue specific (lung granulomas and lymph nodes) immune responses will be correlated with the amount of Mtb bacteria and virus with the imaging findings so that we can better understand the causes of TB-IRIS. Our short term goal is to better understand the pathogenesis of TB-IRIS in this proposal and these findings will ultimately lead to better treatment and prevention of TB-IRIS which is our long term goal.