Mechanisms of SARS-CoV-2 pathogenesis during HIV/SIV infection

项目总结/摘要 COVID-19疫苗接种降低了SARS-CoV-2感染和严重疾病的风险，但近一半的 住院突破性病例发生在免疫功能低下的个体中。艾滋病毒感染是一种独立风险 严重COVID-19、住院和死亡的因素。免疫力低下的人更有可能 延长SARS-CoV-2感染和病毒脱落，增加病毒传播的风险， 以快速进化出更毒的菌株因此，研究SARS-CoV-2的发病机制， 迫切需要免疫抑制来揭示导致严重COVID-19的因素。SARS-CoV-2肺 发病机制的特征是先天性和适应性免疫细胞浸润到肺部并诱导 炎症免疫反应HIV感染过程中炎症和免疫功能障碍的类似机制 感染导致系统性HIV发病和肺部病理。因此，免疫调节失调 HIV感染期间的反应可能导致SARS-CoV-2合并感染期间严重的疾病结局。SARS- CoV-2复制发生在呼吸道和胃肠道粘膜部位， 与COVID-19相关。胃肠道微生物生态失调与加速的 HIV疾病进展以及肺和肠道微生物生态失调在严重COVID-19中的新作用。 鉴于微生物组在维持粘膜功能和稳态方面起着重要作用， HIV感染引起的微生物群落可能导致炎症和免疫激活， 驱动加重SARS-CoV-2的发病机制。在这里，我们将测试的假设，增加免疫力， HIV感染期间的功能障碍和疲惫、炎症和微生物生态失调促进增强 SARS-CoV-2肺部发病机制。我们将利用猪尾猕猴免疫缺陷病毒（SIV） 模型的快速艾滋病毒/艾滋病，并将测试这一假设期间的状态炎症未经治疗的SIV感染， 在原发性和继发性SARS-CoV-2病毒攻击期间。我们将评估SIV诱导的 免疫抑制与肺泡巨噬细胞和中性粒细胞功能改变在SARS-CoV-2发病机制中作用 和肺部病理学。我们将确定艾滋病毒感染是否会导致胃肠道和肺部 微生物生态失调及其与SARS-CoV-2疾病严重程度的关系。最后，我们将确定是否 在HIV感染期间增加的免疫衰竭促进了初级抗病毒SARS产生的缺陷， CoV-2应答损害对异源SAR-CoV-2再攻击的保护。这些研究将 有助于我们理解正常免疫如何驱动SARS-CoV-2肺部病理生理学， 剖析艾滋病毒感染期间免疫反应的扰动如何导致疾病加重。

PROJECT SUMMARY/ABSTRACT COVID-19 vaccination reduces the risk of SARS-CoV-2 infection and severe disease, but almost half of hospitalized breakthrough cases are in immunocompromised individuals. HIV infection is an independent risk factor for severe COVID-19, hospitalization, and mortality. Immunocompromised individuals are more likely to have prolonged SARS-CoV-2 infection and viral shedding, increasing the risk of viral transmission and allowing for rapid evolution of more virulent strains. Therefore, investigating SARS-CoV-2 pathogenesis in the context of immunosuppression is urgently needed to reveal factors driving severe COVID-19. SARS-CoV-2 lung pathogenesis is characterized by infiltration of innate and adaptive immune cells into the lung and induction of an inflammatory immune response. Similar mechanisms of inflammation and immune dysfunction during HIV infection contribute to systemic HIV pathogenesis and lung pathology. Therefore, dysregulation of immune responses during HIV infection could induce severe disease outcomes during SARS-CoV-2 coinfection. SARS- CoV-2 replication occurs in both respiratory and gastrointestinal mucosal sites and enteric symptoms are associated with COVID-19. There is a defined link between gastrointestinal microbial dysbiosis with accelerated HIV disease progression and an emerging role of lung and intestinal microbial dysbiosis with severe COVID-19. Given that the microbiome plays an important role in maintaining mucosal function and homeostasis, shifts in microbial communities due to HIV infection could contribute to inflammation and immune activation that would drive exacerbated SARS-CoV-2 pathogenesis. Here, we will test the hypothesis that increased immune dysfunction and exhaustion, inflammation, and microbial dysbiosis during HIV infection promote enhanced SARS-CoV-2 lung pathogenesis. We will leverage the pigtail macaque simian immunodeficiency virus (SIV) model of rapid HIV/AIDS and will test this hypothesis during a state of inflammatory untreated SIV infection and during primary and secondary SARS-CoV-2 viral challenges. We will evaluate the roles of SIV-induced immunosuppression and altered alveolar macrophage and neutrophil function on SARS-CoV-2 pathogenesis and pulmonary pathology. We will determine whether HIV infection causes gastrointestinal tract and lung microbial dysbiosis and its association with SARS-CoV-2 disease severity. Lastly, we will determine whether increased immune exhaustion during HIV infection promotes deficits in the generation of primary anti-viral SARS- CoV-2 responses that impairs protection from heterologous SAR-CoV-2 re-challenge. These studies will contribute to our understanding of how normal immunity drives SARS-CoV-2 lung pathophysiology and will dissect how perturbations of immune responses during HIV infection contribute to enhanced disease.