小柯机器人

非经典的NF-κB信号能够逆转全身性HIV和SIV潜伏期
2020-01-27 15:36

2020年1月22日,《自然》杂志在线发表了美国北卡罗莱纳大学教堂山分校J. Victor Garcia研究小组的最新成果。他们指出,通过体内非经典的NF-κB信号能够逆转全身性HIV和SIV潜伏期。

据研究人员表示,持久、潜伏感染的静息CD4+T细胞是HIV感染治愈的最大障碍,因为尽管经过抗逆转录病毒疗法(ART)的数十年治疗,这些细胞仍可以持续存在。研究预计表明,要消除艾滋病毒储存库,需要70多年的连续、完全抑制性抗逆转录病毒疗法。或者,将HIV从潜伏状态中诱导可以加速储存库的减少,从而减少根除时间。先前在临床前动物模型和临床试验中重新激活潜在HIV的尝试测量了外周血中HIV的诱导,而对组织贮库的关注最小,并且效果有限。
 
研究人员发现,AZD5582对非经典NF-κB信号通路的激活导致了ART所抑制的被感染人源化骨髓-肝-胸腺小鼠和猕猴的血液和组织中HIV和SIV RNA的表达。对AZD5582处理后来自组织的静息CD4+T细胞的分析显示,猕猴的淋巴结中SIV RNA表达增加以及在人源化小鼠中分析的几乎所有组织(包括淋巴结、胸腺、骨髓、肝和肺)中HIV的强烈诱导。这种有前景的逆转潜伏方法与适当的方法相结合,可以对持续感染的HIV进行系统性清除,从而大大增加了根除HIV的机会。
 
附:英文原文

Title: Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo

Author: Christopher C. Nixon, Maud Mavigner, Gavin C. Sampey, Alyssa D. Brooks, Rae Ann Spagnuolo, David M. Irlbeck, Cameron Mattingly, Phong T. Ho, Nils Schoof, Corinne G. Cammon, Greg K. Tharp, Matthew Kanke, Zhang Wang, Rachel A. Cleary, Amit A. Upadhyay, Chandrav De, Saintedym R. Wills, Shane D. Falcinelli, Cristin Galardi, Hasse Walum, Nathaniel J. Schramm, Jennifer Deutsch, Jeffrey D. Lifson, Christine M. Fennessey, Brandon F. Keele, Sherrie Jean, Sean Maguire, Baolin Liao, Edward P. Browne, Robert G. Ferris, Jessica H. Brehm, David Favre, Thomas H. Vanderford, Steven E. Bosinger, Corbin D. Jones, Jean-Pierre Routy, Nancie M. Archin, David M. Margolis, Angela Wahl, Richard M. Dunham, Guido Silvestri, Ann Chahroudi, J. Victor Garcia

Issue&Volume: 2020-01-22

Abstract: 

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.

DOI: 10.1038/s41586-020-1951-3

Source: https://www.nature.com/articles/s41586-020-1951-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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