病毒性疾病仍然是醫(yī)學(xué)科學(xué)的最大挑戰(zhàn)之一。由于與人類數(shù)千年的協(xié)同進化,，它們利用人類宿主生物學(xué)生存繁榮的能力使他們很難成為醫(yī)學(xué)治療的靶標(biāo),。
北卡羅來納大學(xué)（UNC）教堂山分校的科學(xué)家們與科羅拉多大學(xué)的同事們一起研究,，首次證明一個人類肝細胞中調(diào)節(jié)基因表達的小RNA分子如何被丙型肝炎病毒劫持以確保此病毒的幸存--幫助醫(yī)學(xué)家們理解為什么一個新的抗病毒藥物出現(xiàn)有效的抗病毒作用。
MicroRNAs涉及調(diào)節(jié)細胞內(nèi)基因表達，通常通過阻斷關(guān)鍵蛋白生產(chǎn)或通過使細胞生長和分化時編碼細胞蛋白的信使RNA不穩(wěn)定的方式,。正常地，它們通過下調(diào)基因表達發(fā)揮作用,。研究小組發(fā)現(xiàn),，肝細胞內(nèi)名為miR-122的microRNA與病毒RNA的結(jié)合可導(dǎo)致病毒穩(wěn)定,，促進病毒基因組在肝臟的有效復(fù)制,，支持病毒的生命周期。
"丙型肝炎病毒與miR-122一起做兩件非常有趣的事",，Stanley M. Lemon博士說,，他是醫(yī)學(xué)微生物學(xué)與免疫學(xué)教授,，北卡羅來納大學(xué)綜合癌癥中心和移植免疫學(xué)中心的成員。
"首先,，它進化了與關(guān)鍵調(diào)節(jié)子的一種獨特的關(guān)系,，因為miR-122代表了存在于肝臟中約一半的microRNA。其次,，該病毒已篡奪了通常下調(diào)基因表達來上調(diào)其RNA穩(wěn)定性的過程,，表達其生命周期所需要的病毒蛋白。這是病毒如何為它們自己邪惡目的而顛覆細胞正常有益功能的一個典型例子,。"
由Lemon博士和他的同事在2005年所做的工作有助于示范miR-122是丙型肝炎病毒復(fù)制自己所必需的,，但機制尚不清楚。現(xiàn)在,，UNC的研究小組已經(jīng)指出它是如何工作的,，這有助于解釋一個新的抗病毒藥物如何瞄準病毒。稱為antagomer的藥物,，在肝中結(jié)合并分離miR-122,，然后使病毒基因組不穩(wěn)定，加速其在肝臟中降解,。最新的研究結(jié)果發(fā)表在本周的《PNAS》（ Proceedings of the National Academy of Sciences）上,。
丙型肝炎是一個持續(xù)的公共健康問題，這個病難以測定,，因為癥狀在感染后幾個月到幾年后出現(xiàn),。疾病控制與預(yù)防中心（Centers for Disease Control and Prevention）估計，美國多達400萬人可能長期感染丙型肝炎病毒,，而且大多數(shù)人不知道他們感染此病毒,。超過三分之一的長期攜帶者可能發(fā)展慢性肝病或肝癌，這是一種致命性癌癥,，它因為這種病毒的傳播而正變得日益普遍,。（生物谷bioon.com）
doi:10.1073/pnas.1016606108
PMC:
PMID:
MicroRNA-122 antagonism against hepatitis C virus genotypes 1-6 and reduced efficacy by host RNA insertion or mutations in the HCV 5′ UTR
Yi-Ping Li, Judith M. Gottwein, Troels K. Scheel, Tanja B. Jensen, and Jens Bukh
Abstract MicroRNA-122 (miR-122) is believed to stimulate hepatitis C virus (HCV) replication through interaction with two adjacent sites downstream of stem loop I (SLI) within the HCV 5′ untranslated region (5′ UTR). Recently, it was demonstrated that locked nucleic acid SPC3649-induced miR-122 antagonism suppressed HCV genotype 1a and 1b infection in vivo. However, virus-producing culture systems with 5′ UTR of different HCV genotypes have not been available for testing 5′ UTR-based treatment approaches. Using JFH1-based Core-NS2 genotype recombinants, we developed 5′ UTR-NS2 recombinants of HCV genotypes 1a, 1b, 2a, 2b, 3a, 4a, 5a, and 6a with efficient growth in Huh7.5 cells. Deletion mutagenesis studies demonstrated that the 5′ UTR SLI was essential for genotypes 1-6 infection. However, lack of SLI could be compensated for by insertion of other structured HCV or host RNA sequences, including U3 small nucleolar RNA. We demonstrated that SPC3649-induced miR-122 antagonism had a potent antiviral effect against HCV genotypes 1-6 5′ UTR-NS2 viruses. Strikingly, HCV recombinant virus with substitution of SLI and miR-122 binding site 1 (S1) by the U3 RNA sequence was not affected by miR-122 antagonism; this was attributed to the lack of an intact S1 by reverse genetics studies. Therefore, we engineered the corresponding U3 RNA sequences into S1 and demonstrated that HCV recombinants with wild-type SLI and single or combined mutations at four of eight nucleotides of S1 were viable in Huh7.5 cells. These mutations reduced the efficacy of SPC3649 treatment, indicating that escape variants to miR-122 antagonism-based HCV therapy could potentially occur.
