Analysis of Sin Nombre virus inhibition in lung cells

描述(申请人提供)：肺部是许多急性病毒病原体的目标。其中，汉坦病毒，如新诺布雷病毒(SNV)，代表着一个重要的新出现的传染病问题，被认为是NIAID生物防御倡议的高度优先(A类)病原体。一个主要的担忧是这些病毒的致命性。在欧洲和亚洲，感染经常导致肾综合征出血热(HFRS)，死亡率为1-15%。然而，在美洲，感染是一种严重的汉坦病毒肺综合征(HPS)的原因，这种综合症会导致多达一半的病例出现肺衰竭和死亡。研究表明，HPS患者的肺部有显著的病毒积聚和极高水平的病毒抗原，这与他们参与肺功能恶化的情况是一致的。尽管人们对汉坦病毒感染的了解越来越多，但缺乏明确的治疗方法。为了弥补这一差距，我们的探索性/发育性(R21)研究的重点是分析和开发阻断汉坦病毒在肺细胞中复制的治疗方法。使用新开发的检测方法，我们将评估现有和新型抗病毒药物的效果，如下： 1.汉坦病毒复制核苷抑制剂的分析：将对汉坦病毒的候选核苷抑制剂进行评估，以确定潜在的立即可用的抗病毒药物，并建立与替代抑制剂进行比较的基础。 2.干扰素诱导的病毒抑制的特征：将在没有核苷类似物和存在核苷类似物的情况下测试干扰素α(IFNA)，以评估其效果。 3.新型磷二酸吗啉齐聚物(PMO)抗病毒活性的检测：将检测针对病毒转录和翻译起始的反义PMO。 我们认为，这些探索性研究很有可能导致汉坦病毒介导的肺衰竭的更有效治疗。

DESCRIPTION (provided by applicant): The lungs are a target of a number of acute viral pathogens. Of these, hantaviruses such as the Sin Nombre virus (SNV) represent a significant emerging infectious disease concern and are considered as high priority (Category A) agents for the NIAID biodefense initiative. A major concern is the lethality of these viruses. In Europe and Asia, infections frequently cause a hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of 1-15%. However, in the Americas, infections are the cause of a severe hantavirus pulmonary syndrome (HPS), which leads to pulmonary failure and death in as many as half of the cases. Studies have demonstrated marked accumulations of viruses and extremely high levels of viral antigens in the lungs of HPS patients, consistent with their involvement in the deterioration of lung function. Despite a growing understanding of hantavirus infections, definitive treatments are lacking. To bridge this gap, the focus of our exploratory/developmental (R21) investigations is on the analysis and development of therapeutic approaches to block hantavirus replication in lung cells. Using newly developed assays, we will evaluate the effects of available and of novel antiviral agents, as follows: 1. Analysis of nucleoside inhibitors of hantavirus replication: Candidate nucleoside inhibitors of hantaviruses will be evaluated to identify potential immediately available antivirals, and to establish a basis for comparison with alternative inhibitors. 2. Characterization of interferon-induced virus inhibition: Interferon alpha (IFNa) will be tested in the absence and presence of nucleoside analogues to assess its effects. 3. Examination of novel phosphorodiamidate morpholino oligomer (PMO) antiviral activities: Antisense PMOs targeting virus transcription and translation initiation will be examined. We believe that these exploratory studies have a high probability of leading to more efficient treatment of hantavirus-mediated pulmonary failure.