Inhibition of HIV‐1 multiplication by a modified U7 snRNA inducing Tat and Rev exon skipping
Inhibition of HIV‐1 multiplication by a modified U7 snRNA inducing Tat and Rev exon skipping
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修饰的 U7 snRNA 诱导 Tat 和 Rev 外显子跳跃抑制 HIV-1 增殖
DOI：
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发表时间：
2007
影响因子：
3.5
通讯作者：
D. Schümperli
中科院分区：
文献类型：
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作者：
M. Asparuhova;G. Marti;Songkai Liu;F. Serhan;D. Trono;D. Schümperli
HIV-1调节蛋白TAT和REV是由多个剪接的mRNA编码的，不同的是在内部外显子的开始使用了不同的3‘剪接位点。如果这些内部外显子被跳过，这些基因的表达就应该被抑制，从而抑制HIV-1的复制。我们之前已经开发了一种策略，基于U7小核RNA的反义衍生品，允许我们诱导几乎任何基因的内部外显子跳过。在这里，我们已经成功地应用这种方法来诱导TAT、REV(和Nef)内部外显子的部分跳过。将三个具有功能的U7构建物亚克隆到慢病毒载体中。与不携带U7插入物或不携带U7盒的载体相比，其中两种方法大大降低了慢病毒颗粒的生产效率。这一缺陷可以通过在生产细胞系中共表达来自未剪接的mRNA的REV来部分或完全弥补。在稳定地转导到CEM-SS或CEM T淋巴细胞后，这些构建物中最有效的一个可以抑制HIV-1的复制。尽管这种抑制并不完全，但与另一种抑制艾滋病毒增殖的机制相结合会更有效。因此，这种针对HIV-1调控基因的前mRNA剪接水平的新方法，与其他抗病毒策略相结合，可能是对抗HIV/AIDS的有用的新工具。版权所有©2007 John Wiley&Sons，Ltd.
The HIV‐1 regulatory proteins Tat and Rev are encoded by multiply spliced mRNAs that differ by the use of alternative 3' splice sites at the beginning of the internal exon. If these internal exons are skipped, the expression of these genes, and hence HIV‐1 multiplication, should be inhibited. We have previously developed a strategy, based on antisense derivatives of U7 small nuclear RNA, that allows us to induce the skipping of an internal exon in virtually any gene. Here, we have successfully applied this approach to induce a partial skipping of the Tat, Rev (and Nef) internal exons. Three functional U7 constructs were subcloned into a lentiviral vector. Two of them strongly reduced the efficiency of lentiviral particle production compared to vectors carrying either no U7 insert or unrelated U7 cassettes. This defect could be partly or fully compensated by coexpressing Rev from an unspliced mRNA in the producing cell line. Upon stable transduction into CEM‐SS or CEM T‐lymphocytes, the most efficient of these constructs inhibits HIV‐1 multiplication. Although the inhibition is not complete, it is more efficient in combination with another mechanism inhibiting HIV multiplication. Therefore, this new approach targeting HIV‐1 regulatory genes at the level of pre‐mRNA splicing, in combination with other antiviral strategies, may be a useful new tool in the fight against HIV/AIDS. Copyright © 2007 John Wiley & Sons, Ltd.
影响因子：
12.4
作者：
Li, MJ;Kim, J;Rossi, JJ
通讯作者：
Rossi, JJ
慢病毒载体递送反义 snRNA 后，人地中海贫血红系祖细胞中血红蛋白 A 高水平表达。
影响因子：
20.3
作者：
Vacek,MarlaM;Ma,Hong;Gemignani,Federica;Lacerra,Giuseppina;Kafri,Tal;Kole,Ryszard
通讯作者：
Kole,Ryszard
影响因子：
12.4
作者：
Li, MJ;Bauer, G;Rossi, JJ
通讯作者：
Rossi, JJ