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Great efforts have been made in developing new therapies for HCV infection; however, combination therapy with pegylated IFN\u2010<jats:italic>\u03b1<\/jats:italic> and ribavirin (pegIFN\u2010RBV) remains the first choice of treatment for chronic HCV infection in most countries. The treatment response to pegIFN\u2010RBV remains relatively low. Understanding the molecular mechanisms of persistent HCV infection and pegIFN\u2010RBV resistance will suggest ways of improving the current standard of care and offers new antiviral therapies for both HCV and other viral infections. Recent data suggest that increased expression of hepatic IFN\u2010stimulated genes (ISGs) before treatment is associated with treatment nonresponse in patients chronically infected with HCV. Although ISGs are generally antiviral in nature, in the case of HCV, the virus may exploit some of them to its benefit. This is not unique to HCV: Blockade of type I IFN signaling has been shown to control persistent LCMV infection. Thus, in certain viral infections, preactivation or overactivation of type I IFN signaling may contribute to viral persistence. In this review, we briefly summarize the findings from high\u2010throughput gene expression profiling from patients chronically infected with HCV, then focus on a novel ubiquitin\u2010like signaling pathway (ISG15\/USP18) and its potential role in HCV persistence. Finally, the role of activation of endogenous type I IFN signaling in persistent HCV infection will be discussed in the context of recent studies indicating that blocking IFN signaling controls persistent LCMV infection. Copyright \u00a9 2014 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/rmv.1795","type":"journal-article","created":{"date-parts":[[2014,5,8]],"date-time":"2014-05-08T07:00:51Z","timestamp":1399532451000},"page":"332-342","source":"Crossref","is-referenced-by-count":19,"title":["Activation of endogenous type I IFN signaling contributes to persistent HCV infection"],"prefix":"10.1002","volume":"24","author":[{"given":"Yujia","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Blood Transfusion Chinese Academy of Medical Sciences and Peking Union Medical College  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Blood Transfusion Chinese Academy of Medical Sciences and Peking Union Medical College  Chengdu Sichuan 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