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Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo
Nature ( IF 50.5 ) Pub Date : 2020-01-22 , DOI: 10.1038/s41586-020-1951-3
Christopher C Nixon 1, 2, 3 , Maud Mavigner 4 , Gavin C Sampey 2, 3, 5, 6 , Alyssa D Brooks 4 , Rae Ann Spagnuolo 1, 2, 3 , David M Irlbeck 6, 7 , Cameron Mattingly 4 , Phong T Ho 1, 2, 3 , Nils Schoof 4 , Corinne G Cammon 1, 2, 3 , Greg K Tharp 8 , Matthew Kanke 9, 10 , Zhang Wang 11 , Rachel A Cleary 1, 2, 3 , Amit A Upadhyay 8 , Chandrav De 1, 2, 3 , Saintedym R Wills 2, 3, 5, 6 , Shane D Falcinelli 2, 3, 5, 12 , Cristin Galardi 6, 7 , Hasse Walum 8 , Nathaniel J Schramm 1, 2, 3 , Jennifer Deutsch 11 , Jeffrey D Lifson 13 , Christine M Fennessey 13 , Brandon F Keele 13 , Sherrie Jean 8 , Sean Maguire 11 , Baolin Liao 1, 2, 3, 14 , Edward P Browne 2, 3, 5 , Robert G Ferris 6, 7 , Jessica H Brehm 6, 7 , David Favre 6, 11 , Thomas H Vanderford 8 , Steven E Bosinger 8, 15 , Corbin D Jones 9, 10 , Jean-Pierre Routy 16, 17 , Nancie M Archin 2, 3, 5 , David M Margolis 2, 3, 5, 6, 12, 18 , Angela Wahl 1, 2, 3 , Richard M Dunham 2, 3, 5, 6, 7 , Guido Silvestri 8, 15 , Ann Chahroudi 4, 8, 19 , J Victor Garcia 1, 2, 3
Affiliation  

Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2,3,4,5,6,7,8,9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow–liver–thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal—in combination with appropriate tools for systemic clearance of persistent HIV infection—greatly increases opportunities for HIV eradication.



中文翻译:


通过体内非经典 NF-κB 信号传导系统性 HIV 和 SIV 潜伏期逆转



持久、潜伏感染的静息 CD4 + T 细胞是治愈 HIV 感染的最大障碍,因为尽管经过数十年的抗逆转录病毒疗法 (ART) 治疗,这些细胞仍能持续存在。据估计,需要 70 多年的持续、完全抑制性 ART 才能消除 HIV 病毒库1 。或者,从潜伏状态诱导艾滋病毒可以加速储存库的减少,从而缩短根除时间。先前在临床前动物模型和临床试验中重新激活潜伏HIV的尝试已经测量了外周血中HIV的诱导,很少关注组织储存库,并且效果有限2,3,4,5,6,7,8,9 。在这里,我们展示了 AZD5582 激活非经典 NF-κB 信号通路导致在 ART 抑制的骨髓-肝脏-胸腺 (BLT) 人源化小鼠和恒河猴的血液和组织中诱导 HIV 和 SIV RNA 表达分别感染 HIV 和 SIV 的猕猴。对 AZD5582 治疗后组织中静息 CD4 + T 细胞的分析显示,猕猴淋巴结中 SIV RNA 表达增加,并且在人源化小鼠分析的几乎所有组织中,包括淋巴结、胸腺、骨髓、肝脏和肺,HIV 均被强烈诱导。 。这种有希望的潜伏期逆转方法——与系统清除持续性艾滋病毒感染的适当工具相结合——大大增加了根除艾滋病毒的机会。

更新日期:2020-01-22
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