Ahmed Chulbul M, Martin James P, Johnson Howard M
Department of Microbiology and Cell Science, University of Florida, Museum Road, Gainesville, FL 32611, USA.
J Immunol. 2007 Apr 1;178(7):4576-83. doi: 10.4049/jimmunol.178.7.4576.
We have developed small peptide mimetics of IFN-gamma that can bypass the poxvirus virulence factor B8R protein, which binds to intact IFN-gamma and prevents its interaction with receptor extracellular domain. Thus, these peptides inhibit vaccinia virus replication in cell culture where intact IFN-gamma is ineffective. We demonstrate here that the mouse IFN-gamma-mimetic peptide, IFN-gamma(95-132), protects C57BL/6 mice against overwhelming lethal vaccinia virus infection. The mimetic peptide was synthesized with an attached lipophilic group for penetration of cell plasma membrane. Injection of mimetic i.p. before and at the time of intranasal (10(6) PFU) or i.p. (10(7) PFU) challenge with virus resulted in complete protection at 200 microg of mimetic and 40-60% protection at 5 microg of mimetic. Initiation of treatment of mice with IFN-gamma mimetic up to 2 days postinfection resulted in complete protection against death, whereas initiation of treatment at 6 days postinfection resulted in 40% protection. Administration of mimetic by the oral route also completely protected mice against the intranasal route of a lethal dose of vaccinia virus challenge. In addition to its direct antiviral effect, the mimetic also possessed adjuvant effects in boosting humoral and cellular immunity to vaccinia virus. The combination of antiviral and adjuvant effects by the IFN mimetic probably plays a role in its potent anti-vaccinia virus properties. These results suggest an effective therapeutic against ongoing, lethal poxvirus infections that taps into innate and adaptive host defenses.
我们已经开发出了干扰素-γ的小肽模拟物，其可以绕过痘病毒毒力因子B8R蛋白，该蛋白可与完整的干扰素-γ结合并阻止其与受体细胞外结构域相互作用。因此，这些肽在完整的干扰素-γ无效的细胞培养中可抑制痘苗病毒复制。我们在此证明，小鼠干扰素-γ模拟肽IFN-γ(95 - 132)可保护C57BL/6小鼠免受致死性痘苗病毒的严重感染。模拟肽合成时带有一个亲脂性基团，用于穿透细胞质膜。在经鼻（10⁶ PFU）或腹腔注射（10⁷ PFU）病毒攻击前及攻击时腹腔注射模拟肽，200 μg模拟肽可实现完全保护，5 μg模拟肽可实现40 - 60%的保护。在感染后长达2天开始用干扰素-γ模拟物治疗小鼠可实现完全保护使其免于死亡，而在感染后6天开始治疗可实现40%的保护。经口服途径给予模拟肽也可完全保护小鼠免受致死剂量痘苗病毒经鼻攻击。除了其直接抗病毒作用外，模拟肽在增强针对痘苗病毒的体液免疫和细胞免疫方面还具有佐剂作用。干扰素模拟物的抗病毒和佐剂作用相结合可能在其强大的抗痘苗病毒特性中发挥作用。这些结果提示了一种针对正在进行的致死性痘病毒感染的有效治疗方法，该方法利用了宿主的固有和适应性防御机制。
