Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)
Extended Protection against Phlebovirus Infection Conferred by Recombinant Adenovirus Expressing Consensus Interferon (DEF201)
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DOI：
10.1128/aac.00376-12
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Turner, Jeffrey D.
中科院分区：
文献类型：
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作者：
Gowen, Brian B.;Ennis, Jane;Turner, Jeffrey D.
Punta Toro病毒(PTV；Bunyaviridae，PhleboVirus)与裂谷热病毒(RVFV)有关，裂谷热病毒是一种主要在非洲撒哈拉以南地区导致人和牲畜严重疾病的病原体。最近RVFV范围的扩大以及故意将其释放到幼稚人群中的可能性对公共卫生和农业构成重大威胁。在啮齿动物和非人类灵长类动物中模拟疾病的研究表明，PTV和RVFV对α-干扰素(干扰素-α)的抗病毒作用高度敏感，α-干扰素是天然抗病毒宿主反应的重要组成部分。虽然重组干扰素-α具有很高的治疗价值，但其用于治疗被忽视的热带疾病的有效性受到体内半衰期短和生产成本较高的聚乙二醇化干扰素的阻碍。在这里，我们展示了一次鼻腔注射DEF201后，针对致命的PTV攻击的延长暴露前保护，DEF201是一种复制缺陷的人腺病毒5型载体，其设计是从转导的宿主细胞结构性地表达一致的干扰素-α(c干扰素-α)。作为暴露后对策，DEF201在24小时内给药也是有效的。治疗后8h即可检测到cIFN-α的血清浓度，并持续1周以上。长期的抗静脉病毒预防效果、低生产成本和易于使用使DEF201成为在自然疾病暴发期间进行干预和对抗可能的生物恐怖行为的一种有前途的药物。
Punta Toro virus (PTV; Bunyaviridae, Phlebovirus) is related to Rift Valley fever virus (RVFV), a pathogenic agent which causes severe disease in humans and livestock primarily in the sub-Saharan region of Africa. The recent range expansion of RVFV and the potential for its intentional release into naive populations pose a significant threat to public health and agriculture. Studies modeling disease in rodents and nonhuman primates have shown that PTV and RVFV are highly sensitive to the antiviral effects of alpha interferon (IFN-alpha), an important component of the innate antiviral host response. While recombinant IFN-alpha has high therapeutic value, its utility for the treatment of neglected tropical diseases is hindered by its short in vivo half-life and costly production of longer-lasting pegylated IFNs. Here, we demonstrate extended preexposure protection against lethal PTV challenge following a single intranasal administration of DEF201, which is a replication-deficient human adenovirus type 5 vector engineered to constitutively express consensus IFN-alpha (cIFN-alpha) from transduced host cells. DEF201 was also efficacious when administered within 24 h as a postexposure countermeasure. Serum concentrations of cIFN-alpha could be detected as early as 8 h following treatment and persisted for more than 1 week. The prolonged antiphlebovirus prophylactic effect, low production costs, and ease of administration make DEF201 a promising agent for intervention during natural disease outbreaks and for countering possible bioterrorist acts.