Rapid Immune Restoration and Lung Injury in HIV/TB

 描述(申请人提供)：艾滋病毒-1感染通过摧毁结核分枝杆菌(Mtb)特异性免疫功能，极大地增加了结核病(TB)的风险，因此全球近15%的结核病病例和25%的结核病死亡与艾滋病毒相关。虽然结核病是一种可治疗的疾病，但在那些治愈的人中，它与显著的慢性发病率有关。例如，在肺结核病(PTB)中，尽管获得了微生物治疗，但超过一半的患者仍有肺功能损害。虽然一些患者获得了放射学和症状的完全缓解，但另一些患者则留下了永久性的呼吸道扭曲、持续的咳嗽和严重的慢性呼吸困难。到目前为止，人类研究还没有集中于确定决定长期功能结果的可改变的生物因素。这是一个关键的知识差距，因为了解这种关系可以为开发新的宿主导向疗法提供信息，旨在减少这种全球重要疾病的发病率。艾滋病毒/结核病是一种以免疫抑制和高水平的免疫激活和炎症为特征的疾病状态。虽然成功的结核病和艾滋病毒治疗最终会逆转这些影响，但在开始抗逆转录病毒治疗(ART)的HIV/PTB患者中，涉及肺胶原降解的结核杆菌特异性免疫功能、炎性细胞因子和循环蛋白酶的急剧增加经常发生。坊间报道表明，ART相关的细胞免疫修复可导致明显的肺空洞形成和肺功能恶化。这些数据挑战了这样一种观点，即在肺结核治疗开始后，肺结核患者的肺破坏过程停止，愈合开始。我们假设，在HIV/PTB中，与治疗相关的快速逆转免疫抑制的不良和可改变的影响是肺损伤的恶化。在这项提案中，我们将通过在南非的一项前瞻性队列研究中设定的两个目标来检验这一假设。特定的 目的1将验证ART启动与ART启动后早期肺部炎症增加相关的假说。肺部炎症将通过2-脱氧-2-[18F]-氟-D-葡萄糖(FDG)正电子发射断层扫描/计算机断层扫描(PET-CT)进行连续评估，它可以在ART开始之前和之后直观地定位肺部的炎症。《特定目标2》将验证这样一种假设，即抗逆转录病毒治疗后更快的免疫恢复与永久性肺功能受损有关。通过研究与结核病治疗期间发生的肺损伤相关的免疫学机制，该项目将增加对结核病相关肺损伤的更广泛的了解，并将直接为未来宿主导向疗法在这种疾病中的试验提供信息。

 DESCRIPTION (provided by applicant): By decimating Mycobacterium tuberculosis (Mtb)-specific immune function, HIV-1 infection dramatically increases the risk of tuberculosis (TB), such that nearly 15% of all TB cases and 25% of global TB deaths are HIV-associated. Although TB is a treatable disease, it is associated with significant chronic morbidity among those who are cured. In pulmonary TB (pTB), for example, over half of patients have pulmonary function impairment despite achieving microbiologic cure. While some patients achieve complete radiographic and symptomatic resolution, others are left with permanent distortion of the airways, persistent cough and severe chronic breathlessness. Human studies to date have not focused on identifying modifiable biological factors that determine long-term functional outcome. This is a critical knowledge gap because understanding this relationship could inform development of novel host-directed therapies designed to decrease morbidity in this globally important disease. HIV/TB is a disease state characterized by immunosuppression and high levels of immune activation and inflammation. While successful TB and HIV treatment eventually reverses these effects, dramatic increases in Mtb-specific immune function, inflammatory cytokines and circulating proteases involved in lung collagen degradation frequently occur in patients with HIV/pTB who initiate antiretroviral therapy (ART). Anecdotal reports have indicated that ART-associated cellular immune restoration can lead to overt development of pulmonary cavitation and worsening lung function. These data challenge the notion that the process of lung destruction in TB stops, and healing begins, after pTB treatment initiation. We hypothesize that in HIV/pTB an untoward and modifiable effect of rapid, treatment-related reversal of immunosuppression is worsening of lung injury. In this proposal, we will test this hypothesis via two aims set within a single prospective cohort study in South Africa. Specific Aim 1 will test the hypothesis that ART initiation is associated with increased pulmonary inflammation early after ART initiation. Pulmonary inflammation will be serially assessed by 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET-CT), which can visually localize inflammation in the lung, prior to and after ART initiation. Specific Aim 2 will test the hypothesis that more rapid immune restoration on ART is associated with permanently impaired lung function. By studying immunologic mechanisms associated with incident lung damage during TB treatment, this project will increase understanding of TB-associated lung injury more broadly and will directly inform future trials of host-directed therapies in this disease.