Nature Communications：IL-21抵抗HIV-1病毒感染机制

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      众说周知，HIV-1病毒通过感染和清除人体免疫CD4 T细胞，从而破坏机体的免疫系统。激活的CD4 T细胞能够产生一种白介素——IL-21，IL-21已被发现在慢性病毒感染中发挥抗病毒作用，但其抵抗HIV-1的感染机制并不清楚。

　　最近，由美国康奈尔大学Laurie H.Glimcher教授课题组，发现IL-21能够抑制HIV-1感染CD4 T细胞，而且其抑制作用是通过一种microRNA——miR-29实现的。这一研究成果，在线发表在6月25日的《自然通讯》（Nature Communications）上。
　　　　
　　研究人员先用IL-21孵育人类淋巴器官培养组织（HLACs），然后再用HIV-1感染，发现IL-21预处理培养组织中的CD4 T细胞能够明显抵抗HIV-1的感染。对其机制研究，研究人员先检测了HIV-1限制性因子，如APOBEC3G, SAMHD1 and Tetherin的表达，发现它们的蛋白表达并没有很明显的改变。随后，作者对HIV-1限制性miR-29家族进行了检测，发现IL-21能够特异性的上调miR-29的表达。并且，利用miR-29拮抗核苷酸链处理，能够消除IL-21抵抗HIV-1感染作用。有意思的是，miR-29的表达在病人中也是如此，在正常人和HIV-1“精英控制者”的外周血CD4 T细胞中，miR-29表达正常，而在HIV-1感染病人中，miR-29显著下调。
　　

　　最后，研究人员在人源化小鼠中进行了体内实验。作者首先评价了在新生小鼠移植人类CD34造血干细胞14-18周后HIV-1感染的表型，发现小鼠脾脏和结肠固有层中总CD4 T细胞减少，IL-21和IL-17A产生CD4T细胞也减少，HIV-1感染人源化小鼠能够模拟人体感染环境。研究人员通过在HIV感染前3天尾静脉注射IL-21表达质粒，两周后分析HIV-1感染后病毒扩增情况。结果显示，IL-21确实对HIV具有早期的保护效果。

　　
　   这项研究发现了人体IL-21抵御HIV-1早期感染的一种新机制。不幸的是，HIV-1会损害病人的IL-21产生，阻碍miR-29在CD4T细胞的表达。但这也为抗HIV-1药物和疫苗开发提供了新的思路——如何提高病人体内IL-21的表达来发挥抗病毒作用。

       本文由中国病毒学论坛原创，欢迎转载，转载请注明出处。

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miRNA除了通过miRNA沉默复合体结合于靶基因的3’UTR区域种子序列来起到特殊调控作用外，还有特殊的功能来发挥抗病毒作用。

在2014年的一篇PNAS中，研究人员发现包括miR-146a、miR-17、miR-19及miR-16等在内的miRNA都通过miRNA沉默复合体与HIV-1的Gag蛋白结合，破坏Gag聚合组装, 进而被溶酶体(lysosomes)所降解，抑制病毒的产生。



这一研究对于阻止HIV及其他逆转录病毒自我复制与扩散提供了新的思路，在未来研究者或许可以针对这些miRNA开发设计新型抗逆转录病毒药物。

MicroRNA binding to the HIV-1 Gag protein inhibits Gag assembly and virus production

Antony K. Chen, Prabuddha Sengupta, Kayoko Waki, Schuyler B. Van Engelenburg, Takahiro Ochiya, Sherimay D. Ablan, Eric O. Freed, and Jennifer Lippincott-Schwartz

MicroRNAs (miRNAs) are small, 18–22 nt long, noncoding RNAs that act as potent negative gene regulators in a variety of physiological and pathological processes. To repress gene expression, miRNAs are packaged into RNA-induced silencing complexes (RISCs) that target mRNAs for degradation and/or translational repression in a sequence-specific manner. Recently, miRNAs have been shown to also interact with proteins outside RISCs, impacting cellular processes through mechanisms not involving gene silencing. Here, we define a previously unappreciated activity of miRNAs in inhibiting RNA–protein interactions that in the context of HIV-1 biology blocks HIV virus budding and reduces virus infectivity. This occurs by miRNA binding to the nucleocapsid domain of the Gag protein, the main structural component of HIV-1 virions. The resulting miRNA–Gag complexes interfere with viral–RNA-mediated Gag assembly and viral budding at the plasma membrane, with imperfectly assembled Gag complexes endocytosed and delivered to lysosomes. The blockade of virus production by miRNA is reversed by adding the miRNA’s target mRNA and stimulated by depleting Argonaute-2, suggesting that when miRNAs are not mediating gene silencing, they can block HIV-1 production through disruption of Gag assembly on membranes. Overall, our findings have significant implications for understanding how cells modulate HIV-1 infection by miRNA expression and raise the possibility that miRNAs can function to disrupt RNA-mediated protein assembly processes in other cellular contexts.

http://www.pnas.org/content/111/26/E2676.abstract

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miR-29抗HIV-1作用在08和09年就有报道，发现miR-29能够靶向nef和3‘UTR区域，影响病毒蛋白表达和病毒产生。

Retrovirology. 2008 Dec 23;5:117. doi: 10.1186/1742-4690-5-117.
Human cellular microRNA hsa-miR-29a interferes with viral nef protein expression and HIV-1 replication.
Ahluwalia JK1, Khan SZ, Soni K, Rawat P, Gupta A, Hariharan M, Scaria V, Lalwani M, Pillai B, Mitra D, Brahmachari SK.

Mol Cell. 2009 Jun 26;34(6):696-709. doi: 10.1016/j.molcel.2009.06.003.
Cellular microRNA and P bodies modulate host-HIV-1 interactions.
Nathans R1, Chu CY, Serquina AK, Lu CC, Cao H, Rana TM.

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IL-21 induces antiviral microRNA-29 in CD4 T cells to limit HIV-1 infection

Stanley Adoro,        Juan R. Cubillos-Ruiz,        Xi Chen,        Maud Deruaz,        Vladimir D. Vrbanac,        Minkyung Song,        Suna Park,        Thomas T. Murooka,        Timothy E. Dudek,        Andrew D. Luster,        Andrew M. Tager,        Hendrik Streeck,        Brittany Bowman,        Bruce D. Walker,        Douglas S. Kwon,        Vanja Lazarevic        & Laurie H. Glimcher

Initial events after exposure determine HIV-1 disease progression, underscoring a critical need to understand host mechanisms that interfere with initial viral replication. Although associated with chronic HIV-1 control, it is not known whether interleukin-21 (IL-21) contributes to early HIV-1 immunity. Here we take advantage of tractable primary human lymphoid organ aggregate cultures to show that IL-21 directly suppresses HIV-1 replication, and identify microRNA-29 (miR-29) as an antiviral factor induced by IL-21 in CD4 T cells. IL-21 promotes transcription of all miR-29 species through STAT3, whose binding to putative regulatory regions within the MIR29 gene is enriched by IL-21 signalling. Notably, exogenous IL-21 limits early HIV-1 infection in humanized mice, and lower viremia in vivo is associated with higher miR-29 expression. Together, these findings reveal a novel antiviral IL-21-miR-29 axis that promotes CD4 T-cell-intrinsic resistance to HIV-1 infection, and suggest a role for IL-21 in initial HIV-1 control in vivo.

http://www.nature.com/ncomms/201 ... /ncomms8562.html#f4