整合器复合子单元12 淘汰赛克服了转录阻断,以逆转HIV潜伏时间
Carley N Gray1, Manickam Ashokkumar2,3, Derek H Janssens4
1Department of Microbiology, University of Washington, Seattle, WA, USA.
bioRxiv : the preprint server for biology
|September 11, 2024
概括
针对性 集成器复合体子单元12 (INTS12) 增强了HIV潜伏逆转. 淘汰INTS12可以促进艾滋病毒-1在感染艾滋病毒的人的细胞中重新激活,从而提高潜伏逆转剂的疗效.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
背景情况:
- 潜伏的艾滋病毒储存库对实现艾滋病毒治愈构成了重大挑战.
- 结合AZD5582和I-BET151等潜伏逆转剂 (LRAs),旨在重新激活HIV-1,但它们在艾滋病毒感染者 (PLWH) 中的疗效需要改进.
研究的目的:
- 确定新的目标,以加强HIV潜伏逆转,并与现有的LRA结合.
- 调查整合器综合体在调节HIV-1转录和重新激活中的作用.
主要方法:
- 使用AZD5582和I-BET151采用CRISPR屏幕来识别调节HIV-1重新激活的因素.
- 集成器复合体子单位12 (INTS12) 被确定为一个关键目标.
- 评估了INTS12淘汰赛及其对HIV-1转录,RNA聚合酶II (RNAPII) 占用率和病毒RNA产生的影响,这些都是从PLWH获得的初级CD4 T细胞.
主要成果:
- 在转录水平上,INTS12的淘汰显著改善了HIV-1潜伏逆转,显示出比单独LRA更大的特异性.
- 发现INTS12存在于HIV染色体上,并起到转录延长阻断的作用,防止病毒RNA的全长产生.
- INTS12淘汰赛增强了来自病毒抑制PLWH的CD4T细胞中的HIV-1再激活,并检测到超级生物中的病毒RNA.
- 证明INTS12在很大程度上限制了各种LRA的疗效.
结论:
- 整合器综合体,特别是INTS12,是增强HIV潜伏逆转策略的有希望的目标.
- 向INTS12可以克服当前LRA组合的局限性,并改善PLWH细胞中潜伏HIV-1的重新激活.
- 了解INTS12在转录延长中的作用为开发更有效的HIV治疗干预提供了新的途径.
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