Antiviral Agents as Therapy for SARS

严重急性呼吸综合征(SARS)是一种由一种新型的高度传染性呼吸道疾病引起的 人类冠状病毒(CoV)，命名为SARS-CoV。尽管没有新的现场病例报告 自2003年以来，该病毒继续存在于自然界，对其回归构成威胁。截至目前，有效 没有针对SARS的治疗措施，因此开发有效的抗病毒药物 治疗和疫苗势在必行。这种应用的主要目的是建立有效的抗病毒药物。 针对未来SARS暴发的治疗。动物模型是临床前安全性评估的关键， 候选抗病毒药物和疫苗的免疫原性和有效性。创建节约型动物 SARS冠状病毒感染模型，我们获得了表达人血管紧张素的转基因小鼠系 转换酶2(HACE2)，SARS冠状病毒的功能性受体。重要的是，这些hACE2转基因 家系对SARS-CoV感染高度易感，表现出一致的临床表现和 死亡，使它们优于现有的SARS模型(即非人灵长类动物，雪貂， 仓鼠和老鼠)。在几个转基因系中，AC70系具有最好的特性 关于SARS-CoV的传染性和组织学、临床表现、组织病理学、炎症性 对感染的反应和死亡率。为了实现这一目标，我在本申请中建议 为了评估一些抗病毒药物的疗效，包括干扰素(即干扰素-a和干扰素-γ)， 利巴韦林和免疫血浆，在这一创新和高度敏感的转基因小鼠模型中。这些 之所以选择抗病毒药物，是因为它们被经验地用于治疗SARS患者，导致 2002-2003年爆发疫情期间的轶事好处。他们单独或联合治疗SARS的效果 将以高度随机和受控的方式仔细评估这些转基因药物的组合 小鼠，以临床、病毒学、病理和炎症变化以及死亡率为标准。如果 适用的，我将扩大这个项目，以包括新的先导化合物，如蛋白酶抑制剂，化合物 防止病毒进入，用于SARS-CoV复制的siRNA，以及需要纳入本研究的疫苗。 提出了四个具体目标：1)确定选定的抗病毒药物的无毒剂量 治疗SARS冠状病毒感染的疗效观察。2)确定最理想的治疗方法 单独使用抗病毒药物的方案。3)评价免疫血浆/血清治疗慢性粒细胞白血病的疗效。 SARS-CoV感染和4)研究选定的联合治疗的治疗潜力 抗病毒药物。在完成拟议的研究后，通过密切和富有成效的导师与受训人员互动， 不仅期望在抗病毒检测方面获得广泛的科学知识和实践经验，而且 此外，研究结果还确定了有效的抗SARS疗法。

Severe acute respiratory syndrome (SARS) is a highly contagious respiratory disease caused by a novel human coronavirus (CoV), designated SARS-CoV. Although there have been no new reported field cases since 2003, this virus continues to exist in the nature, posing a threat for its return. To date, effective therapeutic measures against SARS are not available, thus making the development of effective antiviral therapy and vaccines imperative. The main objective of this application is to establish effective antiviral therapy against future SARS outbreaks. Animal models are critical for preclinical evaluation of the safety, immunogenicity, and efficacy of candidate antiviral drugs and vaccines. To establish an economical animal model for SARS-CoV infection, we generated transgenic mouse lineages expressing human angiotensin converting enzyme 2 (hACE2), a functional receptor of SARS-CoV. Importantly, these hACE2 transgenic lineages were highly susceptible to SARS-CoV infection, showing consistent clinical manifestations and death, making them superior to existing models described for SARS (i.e., nonhuman primates, ferrets, hamsters, and mice). Among several transgenic lineages, the AC70 lineage is the best characterized with regard to the infectivity and tissue of SARS-CoV, clinical manifestations, histopathology, inflammatory responses, and mortality, in response to infection. To accomplish this objective, I propose in this application to evaluate the therapeutic efficacy of some antiviral agents, including interferons (i.e., IFN-a and IFN-y), ribavirin, and immune plasma, in this innovative and highly sensitive transgenic mouse model. These antiviral agents are selected, because they were used empirically in treating SARS patients, resulting in anecdotal benefits during the explosive outbreak in 2002-2003. Their anti-SARS efficacy alone or in combination will be carefully assessed in a highly randomized and controlled fashion in these transgenic mice, using clinical, virological, pathological, and inflammatory changes, along with the mortality as criteria. If applicable, I will extend this project to include new lead compounds, such as protease inhibitors, compounds that prevent viral entry, siRNA for SARS-CoV replication, and vaccines that warrant inclusion in this study. Four specific aims are proposed: 1) Determine the nontoxic dosages of selected antiviral agents with therapeutic efficacy against SARS-CoV infection. 2) Determine the most optimal therapeutic treatment regimen of individual antiviral agents. 3) Evaluate the therapeutic efficacy of immune plasma/serum against SARS-CoV infection and 4) Investigate the therapeutic potentials of combination treatments of selected antiviral agents. Upon completion of proposed studies, with close and productive mentor-trainee interactions, anticipate not only gaining extensive scientific knowledge and hands-on experience in antiviral testing, but also research results identifying effective anti-SARS therapies.