Investigating the role of altered lung microbiome in fueling Th17 mediated airway inflammation in COPD among HIV-infected individual

摘要 慢性阻塞性肺疾病（COPD）在艾滋病毒感染者中的患病率正在上升 由于抗逆转录病毒疗法（ART）的广泛使用，这一人群的寿命延长。与 撒哈拉以南非洲是艾滋病病毒携带者密度最高的地区， 发病率和死亡率。尽管病毒受到抑制，但尚不完全清楚是什么驱动了肺加速 这一人群的功能下降。在强烈暴露于环境的侮辱中， 开发了强大的保护机制，保护气道微环境，具有高度专业化的 肺部固有和适应性免疫细胞对抗病原体。然而，这些保护机制 随着年龄的增长而恶化，导致肺功能进行性下降和COPD发展。这种下降是 在慢性HIV感染的情况下更糟。尽管缺乏确凿的证据，持续的气道免疫 PLWH之间的激活可能驱动气道免疫衰老、炎症和进行性肺损伤。 功能衰退。很可能在慢性HIV的情况下，T细胞免疫库的收缩 （免疫多样性）增加了对感染的易感性，这会导致慢性炎症，免疫 疲惫和衰老。在该补充申请中，我们旨在研究HIV对远端细胞的影响。 慢性阻塞性肺疾病患者气道免疫衰老和炎症。我们假设：（1）慢性 HIV感染加速气道T细胞受体多样性的年龄依赖性收缩;（2） 减少的多样性与气道炎症和肺功能差（低FEV 1和FVC）相关。 我们将使用来自我们目前正在进行的母R21研究的支气管肺泡灌洗样本来：（1）确定 慢性HIV对气道TCR多样性影响和（2）气道TCR多样性指数与 BAL上清液中炎性细胞因子的含量。这一初步数据将为气道的研究提供依据 炎症之间的PLWH，补充我们的父母R21的目的，调查之间的关联， HIV感染的COPD患者远端气道中的肺微生物组和免疫特征 乌干达艾滋病毒控制队列。

Abstract Chronic Obstructive Pulmonary Disease (COPD) is increasing in prevalence among people living with HIV (PLWH) as the widespread use of antiretroviral therapy (ART) has increased longevity in this population. With the highest density of PLWH, Sub-Saharan Africa has experienced dramatic increases in COPD-related morbidity and mortality. Despite viral suppression, it’s not fully known what drives accelerated lung function decline in this population. Amidst intense exposure to environmental insults, the airways have developed robust protective mechanisms which preserve the airway microenvironment, with highly specialized lung-resident innate and adaptive immune cells fighting off pathogens. However, these protective mechanisms deteriorate with age, resulting in a progressive decline in lung function and COPD development. This decline is worse in the setting of chronic HIV infection. Despite a lack of conclusive evidence, persistent airway immune activation among PLWH possibly drives airway immunosenescence, inflammaging, and progressive lung function decline. It is probable that in the setting of chronic HIV, contraction of the T-cell immune repertoire (immune diversity) increases susceptibility to infections, which drives chronic inflammation, immune exhaustion, and senescence. In this supplementary application, we aim to investigate the effect of HIV on distal airway immunosenescence and inflammaging among individuals with COPD. We hypothesize that: (1) chronic HIV infection accelerates age-dependent contraction of airway T cell receptor diversity; (2) and this reduced diversity is associated with airway inflammation and poor lung function (low FEV1 and FVC). We will use broncho-alveolar lavage samples from our currently running parent R21 study to; (1) determine the effect of chronic HIV on airway TCR diversity and (2) correlate airway TCR diversity indices with levels of inflammaging cytokines in BAL supernatant. This preliminary data will provide a basis to investigate airway inflammaging among PLWH, supplementing our parent R21 objectives of investigating the association between lung microbiome and immune profile in the distal airways of HIV-infected individuals with COPD in a viremically controlled Ugandan HIV cohort.