Pan Qiuwei, Henry Scot D, Metselaar Herold J, Scholte Bob, Kwekkeboom Jaap, Tilanus Hugo W, Janssen Harry L A, van der Laan Luc J W
Department of Gastroenterology&Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
J Mol Med (Berl). 2009 Jul;87(7):713-22. doi: 10.1007/s00109-009-0470-3. Epub 2009 Apr 30.
The current standard interferon-alpha (IFN-alpha)-based therapy for chronic hepatitis C virus (HCV) infection is only effective in approximately half of the patients, prompting the need for alternative treatments. RNA interference (RNAi) represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in infection. Monotherapy of RNAi, however, may lead to therapeutic resistance by mutational escape of the virus. Here, we proposed that combining lentiviral vector-mediated RNAi and IFN-alpha could be more effective and avoid therapeutic resistance. In this study, we found that IFN-alpha treatment did not interfere with RNAi-mediated gene silencing. RNAi and IFN-alpha act independently on HCV replication showing combined antiviral activity when used simultaneously or sequentially. Transduction of mouse hepatocytes in vivo and in vitro was not effected by IFN-alpha treatment. In conclusion, RNAi and IFN-alpha can be effectively combined without cross-interference and may represent a promising combinational strategy for the treatment of hepatitis C.
目前基于α干扰素（IFN-α）的慢性丙型肝炎病毒（HCV）感染标准疗法仅对约一半的患者有效，因此需要其他治疗方法。RNA干扰（RNAi）是一种通过序列特异性靶向参与感染的病毒或宿主因子来对抗HCV的新方法。然而，RNAi单药治疗可能会因病毒的突变逃逸而导致治疗耐药性。在此，我们提出慢病毒载体介导的RNAi与IFN-α联合使用可能更有效且可避免治疗耐药性。在本研究中，我们发现IFN-α治疗并不干扰RNAi介导的基因沉默。RNAi和IFN-α对HCV复制独立起作用，同时或序贯使用时显示出联合抗病毒活性。体内和体外IFN-α治疗均不影响小鼠肝细胞的转导。总之，RNAi和IFN-α可有效联合且无交叉干扰，可能代表一种有前景的丙型肝炎治疗联合策略。
