Defective viral genomes in RSV pathogenesis

总结 对调节病毒发病机制的认识不足限制了我们控制病毒感染的能力。 减少病毒感染，减轻公共卫生负担。复制回型非标准病毒基因组 在病毒感染期间产生的cbVG是呼吸道感染的抗病毒免疫的主要诱导物。 体外、小鼠和人中的合胞病毒（RSV）。最重要的是，我们最近报道说， RSV复制过程中产生的病毒显著影响儿童和成人感染的临床结果。 这些数据表明，cbVG是病毒发病机制的关键决定因素，并且它们的活性可以被抑制。 来最大限度地减少病毒相关疾病。 很明显，病毒与宿主的相互作用是复杂的，解开这种复杂性是至关重要的， 确定更好的疾病严重程度预测因子以及更好的治疗策略。更好地了解 影响cbVG生成和活动的因素对于利用它们作为工具是必要的， 减少RSV和相关病毒的公共卫生负担。在原始提案资助的研究中，我们 证明cbVG的存在严重影响RSV发病机制。虽然检测到cbVG很快 在感染后，cbVG的迟发或持续存在与更严重的疾病有关， 严重的疾病。这里提出的研究，直接遵循这些数据，并专注于调查病毒和宿主 影响CBVG生成和活性的因素。为了做到这一点，我们将表征存在于 人类呼吸道分泌物，我们将研究它们的功能和与不同临床结果的关联。 这项研究将提供第一个全面的调查自然发生的cbVG物种，并将 确定决定其保护或潜在致病功能的独特特征（目标1）。我们还将 评估已知RSV风险因素对cbVG生成的影响，以确定cbVG的宿主决定因素 积累，我们将进行概念验证实验，以测试cbVG是否可以安全地用于 在高风险环境中尽量减少病毒引起的疾病（目标2）。最后，我们将测试宿主免疫的作用， 在晚期或长期cbVG患者中驱动疾病的偏倚，并将确定潜在的治疗靶点 在这些条件下减少疾病（目标3）。

Summary Poor understanding of the mechanisms that modulate virus pathogenesis limits our ability to control viral infections and reduce their public health burden. Non-standard viral genomes of the copy-back type (cbVGs) that are generated during viral infections are the primary inducers of antiviral immunity to respiratory syncytial virus (RSV) in vitro, in mice, and in humans. Most importantly, we recently reported that cbVGs generated during RSV replication significantly impact the clinical outcome of infection in children and adults. These data suggest that cbVGs are key determinants of viral pathogenesis and that their activity can be harnessed to minimize viral-associated disease. It's clear that the virus host-interaction is complex, and it is essential to untangle this complexity to identify better predictors of disease severity as well as better therapeutic strategies. A better understanding of the factors that influence the generation and activity of cbVGs is necessary for exploiting them as a tool for reducing the public health burden of RSV and related viruses. In studies funded in the original proposal, we demonstrated that the presence of cbVG critically impact RSV pathogenesis. While detection of cbVGs soon after infection is protective from severe disease, late or sustained presence of cbVGs associates with more severe disease. Studies proposed here, directly follow these data and focus on investigating viral and host factors that impact cbVG generation and activity. To do this, we will characterize the cbVG species present in human respiratory secretions and we will study their function and association with distinct clinical outcomes. This study will provide the first comprehensive investigation of naturally occurring cbVG species and will identify unique features that determine their protective or potentially pathogenic functions (Aim 1). We will also assess the impact of known RSV risk factors on cbVG generation to identify host determinants of cbVG accumulation, and we will perform proof of concept experiments to test if cbVGs can be safely used to minimize virus-induced disease in high-risk settings (Aim 2). Lastly, we will test the role of the host immune bias in driving disease in patients with late or prolonged cbVGs and will identify potential targets for treatment to reduce disease in these conditions (Aim 3).