缺氧诱导因子（HIF）是转录因子，调节细胞对低氧环境的适应能力，使细胞能够在低氧环境中存活。病毒进化出稳定的该途径以促进成功的病毒感染，因此调节HIF可以作为一种新的抗病毒策略。我们在先前的体外研究中证实了呼吸道合胞病毒（RSV）能够在正常氧条件下稳定HIF，抑制HIF-1α会导致病毒复制减少。尽管已经测试或批准了几种调节HIF的化合物在其他非感染模型中的使用，但对其在呼吸道病毒感染相关动物模型中的功效知之甚少。本研究旨在评估抗HIF-1α（PX478）和抗HIF-2α（PT2385）在感染RSV BALB/c小鼠中的疾病调节性能和抗病毒潜力。我们发现，抑制HIF-1α会加重临床疾病参数，同时改善气道功能。此外，抗HIF-1α可显著降低RSV复制的早期和高峰时点的病毒滴度，但每天给药后病毒清除能力下降，而每隔一天给药则不会。相反，抑制HIF-2α与临床参数的改善相关，对气道功能无影响，并改善间质性肺炎。此外，抗HIF-2α还可以减少肺部病毒复制的早期和高峰期，而不会影响病毒清除。肺部细胞的分析发现在T细胞组分中存在显著的改变，这与肺部病理学和病毒滴度的变化相关，这是对每种HIF抑制剂给药反应的结果。这些数据突显了HIF在RSV感染中的复杂作用，并强调了对治疗的谨慎考虑的必要性。HIF治疗药物的药理学应用主要集中在癌症、自身免疫性疾病和非感染性肺损伤的各种模型中进行研究。由于它们在几个第4期临床试验中的使用，这些化合物的安全性和成功性得到了强调。自2000年以来，许多研究已经证明了HIF抑制剂在上皮细胞系中的抗病毒潜力，然而还没有研究在与呼吸道病毒感染相关的动物模型中抑制HIF的治疗结果。随着人们对药物再定位的兴趣越来越浓厚，我们的研究强调了在包含上皮和免疫组分的复杂生物模型中测试已批准或废弃药物在新条件下的重要性。此外，当前研究揭示了HIF在RSV疾病发病机制中的新角色。这些数据共同证明了免疫调节在RSV感染中的关键机制，并进一步促进了治疗方法的开发。

Hypoxia-inducible-factors (HIF) are transcription factors that regulate cellular adaptation to hypoxic conditions, enabling cells to survive in low-oxygen environments. Viruses have evolved to stabilize this pathway to promote successful viral infection, therefore modulation of HIFs could represent a novel antiviral strategy. In previous in vitro studies, we demonstrate respiratory syncytial virus (RSV), a leading cause of respiratory illness, to stabilize HIFs under normoxic conditions, with inhibition of HIF-1α resulting in reduced viral replication. Despite several HIF modulating compounds being tested/approved for use in other non-infectious models, little is known about their efficacy against respiratory viruses using relevant animal models. This study aimed to characterize the disease modulating properties and antiviral potential of anti-HIF-1α (PX478) and anti-HIF-2α (PT2385) in RSV-infected BALB/c mice. We found inhibition of HIF-1α to worsen clinical disease parameters, while simultaneously improving airway function. Additionally, anti-HIF-1α results in significantly reduced viral titer at early and peak time points of RSV replication, followed by a loss in viral clearance when given every day, but not every-other-day. In contrast, inhibition of HIF-2α was associated with improved clinical parameters, with no changes in airway function, and amelioration of interstitial pneumonia. Furthermore, anti-HIF-2α reduced early and peak lung viral replication, with no impaired viral clearance. Analysis of lung cells found significant modification in the T cell compartment that correlated with changes in lung pathology and viral titers in response to each HIF inhibitor administration. These data underscore the complex role of HIFs in RSV infection and highlight the need for careful therapeutic consideration.The pharmacological use of HIF therapeutics has largely been investigated with various models of cancer, autoimmunity, and non-infectious lung damage. The safety and success of these compounds is emphasized by their use in several phase-4 clinical trials. Since the early 2000s, numerous studies have demonstrated the antiviral potential of HIF inhibitors in epithelial cell lines, however, there are no studies characterizing the therapeutic outcomes of suppressing HIF during a viral respiratory infection in a relevant animal model. With the growing interest in drug repositioning, our research emphasizes the importance of testing approved or abandoned therapeutics under the new conditions in a complex biological model encompassing both the epithelial and immune compartments. Moreover, the current study uncovers a novel role of HIFs in the pathogenesis of RSV disease. These data collectively demonstrate a key mechanism in immune regulation during RSV infection that can further therapeutic development.