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诺奇3删除调节HIV-1基因表达和全身炎症,以改善慢性脏病

Mackenzie Thornton¹, Nicole Sommer¹, Mercedes McGonigle¹

¹Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.

Disease models & mechanisms

|February 6, 2025

概括

向Notch3激活显著降低了HIV-1感染小鼠的损伤和死亡率. 这种Notch3通路在艾滋病毒相关的脏疾病和炎症中起着关键作用.

科学领域:

免疫学免疫学免疫学
病毒学病毒学
腎臟病學 (nephrology) 是一種醫學專業.

背景情况:

抗逆转录病毒疗法 (ART) 可以降低HIV-1的发病率,但不能消除潜在的感染,导致慢性炎症和并发症.
艾滋病毒-1相关性病 (HIVAN) 是一种严重的并发症,其特征是炎和损伤.
需要新的治疗策略来应对持续的病毒活动和炎症,尽管ART.

研究的目的:

研究Notch3激活在HIV-1相关病中的作用.
确定是否向NOTCH3激活可以作为艾滋病毒相关慢性病的有效治疗方法.

主要方法:

使用了HIV-1转基因小鼠模型 (HIV-Tg26) 并生成了Notch3淘汰赛 (Tg-N3KO) 变体.
评估了HIV-Tg26和Tg-N3KO小鼠的损伤,皮肤病变,死亡率,浸细胞和HIV基因表达.
研究了Notch3和HIV长终端重复 (LTR) 促进体之间的相互作用.
分析了骨髓衍生的巨细胞和全身炎症标志物 (TNF,MCP-1) 中的Notch3激活.

主要成果:

与HIV-Tg26小鼠相比,Tg-N3KO小鼠的损伤,皮肤病变和死亡率显著降低.
诺奇3删除导致内入细胞减少和艾滋病毒基因的表达减少.
发现Notch3激活了HIV的LTR促进体,而HIV-1诱导增加了Notch3的激活,这表明有一个反循环.
在HIV-Tg26小鼠中观察到系统性Notch3激活,在Tg-N3KO小鼠中降低了TNF和MCP-1水平.

结论:

在与艾滋病毒相关的慢性病中,Notch3删除/抑制显示出双重治疗效果.
针对Notch3可能为管理HIVAN和潜在的其他艾滋病毒相关病理提供了一个有希望的策略.
在Notch3和HIV-1之间发现的反机制强调了治疗干预的关键途径.

关键词:

艾滋病病毒-1 艾滋病病毒-1 脏 - 脏 - 脏没有3ch3

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