PDF(Pubmed)
Abstract：
Argentine hemorrhagic fever, caused by Junín virus (JUNV), is the most common of the South American arenaviral hemorrhagic fevers. The disease has a case fatality rate of 15-30% in untreated patients. Although early intervention with immune plasma is effective, diminishing stocks and limited availability outside of Argentina underscores the need for new therapeutics. Ideally, these would be broadly active agents effective against all the pathogenic arenaviruses. The fusion inhibitor LHF-535 and the nucleoside analog favipiravir have shown promise in animal models of Lassa fever, a disease endemic in parts of Africa and the most prominent of the arenaviral hemorrhagic fevers. Against JUNV, a high dose of favipiravir is required to achieve protection in the gold-standard guinea pig infection model. Here, we demonstrate a synergistic effect by the coadministration of LHF-535 with a sub-optimal dose of favipiravir in guinea pigs challenged with JUNV. Administered individually, LHF-535 and sub-optimal favipiravir only delayed the onset of severe disease. However, combined dosing of the drugs afforded complete protection against lethal JUNV infection in guinea pigs. The benefits of the drug combination were also evident by the absence of viremia and infectious virus in tissues compared to guinea pigs treated with only the placebos. Thus, combined targeting of JUNV-endosomal membrane fusion and the viral polymerase with pan-arenaviral LHF-535 and favipiravir may expand their indication beyond Lassa fever, providing a significant barrier to drug resistance.
摘要：
阿根廷出血热,由Junín病毒（JUNV）引起，是南美沙粒病毒性出血热中最常见的一种。该疾病在未经治疗的患者中具有15-30%的病死率。尽管免疫血浆的早期干预是有效的，阿根廷以外的库存减少和供应有限，突显了对新疗法的需求。理想情况下,这些将是对所有致病性沙粒病毒有效的广泛活性药物。融合抑制剂LHF-535和核苷类似物favipravir在拉沙热的动物模型中显示出希望，一种在非洲部分地区流行的疾病，也是最突出的沙粒病毒性出血热。反对JUNV，在金标准豚鼠感染模型中，需要高剂量的favipirravir才能达到保护作用。这里,在接受JUNV攻击的豚鼠中,我们证明了LHF-535与次优剂量的favipiravir联合给药的协同作用.单独管理，LHF-535和次优favipiravir仅延迟严重疾病的发作。然而,这些药物的联合给药在豚鼠中提供了对致死性JUNV感染的完全保护。与仅用安慰剂治疗的豚鼠相比,通过在组织中不存在病毒血症和感染性病毒,药物组合的益处也是明显的。因此，JUNV-内体膜融合体和病毒聚合酶与泛沙粒病毒LHF-535和favipiravir的联合靶向可能会扩大其适应症，超越拉沙热，提供了显著的耐药性障碍。
