Griffithsin Protects Mice from Genital Herpes by Preventing Cell-to-Cell Spread
Griffithsin Protects Mice from Genital Herpes by Preventing Cell-to-Cell Spread
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DOI：
10.1128/jvi.00012-13
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发表时间：
2013-06-01
影响因子：
5.4
通讯作者：
Herold, Betsy C.
中科院分区：
文献类型：
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作者：
Nixon, Briana;Stefanidou, Martha;Herold, Betsy C.
Griffithsin结合gp 120上的N-连接聚糖以防止HIV进入，具有任何抗病毒凝集素所描述的最有效的HIV-1抑制活性，并且正在开发用于局部暴露前预防。目前的研究旨在通过探索其对单纯疱疹病毒2型（HSV-2）的活性，进一步评估其潜力，HSV-2是HIV获得的辅助因子，在体外和小鼠模型中。通过检查其对极化培养物中上皮屏障完整性的影响，并测试重复阴道内给药是否增强小鼠对生殖器疱疹的易感性，评价了安全性。如果在病毒进入期间存在，Griffithsin显示出对HSV-2的适度抑制活性，但如果在进入后存在，则完全阻断空斑形成，减小空斑大小，并防止细胞间传播。这些体外研究结果表明，在用0.1% griffithsin凝胶治疗的小鼠中，对生殖器疱疹具有显著的保护作用。Griffithsin而不是安慰剂凝胶，阻止了病毒传播（用表达内切酶的病毒观察），显著降低了疾病评分，并导致更高的存活率（P < 0.05，对数秩检验）。当HSV-2被引入精浆时，保护作用持续存在。尽管格里菲辛在极化培养物中引发了跨上皮电阻的小幅下降，但这并没有导致艾滋病毒从顶室迁移到基底侧室的能力显着增加，也没有导致接受格里菲辛凝胶治疗的小鼠对HSV-2的易感性增加7天。这些发现表明，griffithsin通过阻断细胞间传播的独特机制抑制HSV-2，并支持其进一步开发用于HIV和HSV-2预防。
Griffithsin, which binds N-linked glycans on gp120 to prevent HIV entry, has the most potent HIV-1 inhibitory activity described for any antiviral lectin and is being developed for topical preexposure prophylaxis. The current studies were designed to further assess its potential by exploring its activity against herpes simplex virus 2 (HSV-2), a cofactor for HIV acquisition, in vitro and in a murine model. Safety was evaluated by examining its impact on epithelial barrier integrity in polarized cultures and testing whether repeated intravaginal dosing potentiates the susceptibility of mice to genital herpes. Griffithsin displayed modest inhibitory activity against HSV-2 if present during viral entry but completely blocked plaque formation if present postentry, reduced plaque size, and prevented cell-to-cell spread. These in vitro findings translated to significant protection against genital herpes in mice treated with 0.1% griffithsin gel. Griffithsin, but not placebo gel, prevented viral spread (visualized with a luciferase-expressing virus), significantly reduced disease scores, and resulted in greater survival (P < 0.05, log rank test). Protection persisted when HSV-2 was introduced in seminal plasma. Although griffithsin triggered a small decline in transepithelial electrical resistance in polarized cultures, this did not translate to any significant increase in the ability of HIV to migrate from the apical to the basolateral chamber nor to an increase in susceptibility to HSV-2 in mice treated with griffithsin gel for 7 days. These findings demonstrate that griffithsin inhibits HSV-2 by a unique mechanism of blocking cell-to-cell spread and support its further development for HIV and HSV-2 prevention.