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Proteasomal Inhibition Potentiates Latent HIV Reactivation.
AIDS Research and Human Retroviruses ( IF 1.5 ) Pub Date : 2020-10-05 , DOI: 10.1089/aid.2020.0040
Daniele C Cary 1 , B Matija Peterlin 1
Affiliation  

Despite the success of antiretroviral therapy (ART), ART fails to eradicate the virus and HIV cure has remained beyond the reach of current treatments. ART targets replicating virally infected but not latently infected cells, which have limited expression of factors important for proliferation and cellular activity, including positive transcription elongation factor b (P-TEFb) and nuclear factor κB (NF-κB). Levels of the cyclin T1 (CycT1) subunit of P-TEFb are low to absent in resting T cells, and treatment with proteasome inhibitors (PIs) increases CycT1 protein levels to those of proliferating T cells. In this study, the clinically approved PI bortezomib reactivated latent HIV in latently infected primary CD4+ T cells. Bortezomib not only increased levels of CycT1 but also activated NF-κB. Strikingly, as opposed to most currently researched latency reversing agents (LRAs), bortezomib did not require a second LRA to potently reactivate latent HIV. Effects of bortezomib on resting T cells and reactivation of HIV suggest a possible direction for future attempts to diminish the viral reservoir in HIV+ individuals.

中文翻译:

蛋白酶体抑制增强潜伏的 HIV 再激活。

尽管抗逆转录病毒疗法 (ART) 取得了成功,但 ART 未能根除该病毒,而且目前的治疗方法仍然无法治愈 HIV。ART 的目标是复制病毒感染而非潜伏感染的细胞,这些细胞对增殖和细胞活性重要的因子表达有限,包括正转录延伸因子 b (P-TEFb) 和核因子 κB (NF-κB)。P-TEFb 的细胞周期蛋白 T1 (CycT1) 亚基的水平在静息 T 细胞中很低甚至不存在,并且蛋白酶体抑制剂 (PI) 处理使 CycT1 蛋白水平增加到增殖 T 细胞的水平。在这项研究中,临床批准的 PI 硼替佐米重新激活了潜伏感染的原代 CD4+ T 细胞中的潜伏 HIV。硼替佐米不仅增加了 CycT1 的水平,还激活了 NF-κB。引人注目的是,与目前大多数研究的潜伏逆转剂 (LRA) 不同,硼替佐米不需要第二个 LRA 即可有效地重新激活潜伏的 HIV。硼替佐米对静息 T 细胞和 HIV 再激活的影响为未来减少 HIV+ 个体病毒库的尝试提供了可能的方向。
更新日期:2020-10-07
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