Activation of endogenous type I IFN signaling contributes to persistent HCV infection

Abstract

HCV infection is a major world health problem, leading to both end-stage liver disease and primary liver cancer. Great efforts have been made in developing new therapies for HCV infection; however, combination therapy with pegylated IFN-α and ribavirin (pegIFN-RBV) remains the first choice of treatment for chronic HCV infection in most countries. The treatment response to pegIFN-RBV remains relatively low. Understanding the molecular mechanisms of persistent HCV infection and pegIFN-RBV 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-stimulated 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-throughput gene expression profiling from patients chronically infected with HCV, then focus on a novel ubiquitin-like 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.

Early IFN type I response: Learning from microbial evasion strategies

“…USP18 is, indeed, stabilized by ISG15 in an unconjugated free form [248]. In this respect, the suggested potential role of the ISG15/USP18 pathway in HCV persistence is consistent with the observation that increased expression of hepatic ISGs before IFN treatment is associated with an absent or poor response in patients chronically infected with HCV [249]. Thus, ISG15/USP18 pathway might explain the paradox that the preactivation of the endogenous IFN system, while fails to clear the infection, instead, may stimulate HCV production and blunt the effect of exogenous IFN-I.…”

Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus

“…Furthermore, the pattern of ISG expression differs in response to acute virus infection or IFN treatment as compared to chronic virus infection (Li et al, 2014; Wilson et al, 2013) or diseases involving chronic type I IFN production, including some cancers (Cheon et al, 2014). Thus, the role of ISGs in apoptosis induction in response to VSV infection may be different in cancers with constitutive versus inducible expression of ISGs.…”

Multiple functions of USP18

“…14 The antiviral effect is not due to enhanced ISGylation of ISG15 in the absence of USP18, because Isg15-deficient mice do not exhibit any antiviral impairment after infection with LCMV or VSV. 56 In Addition, Usp18 knockout mice exhibit less replication of several other viruses, such as HBV, 61,62 Sindbis virus, 63 influenza B virus, 46 HIV, 64 and others in which the ISGylation pathway is involved [65][66][67][68][69] (Table 2).…”