Morphine Withdrawal Enhances Hepatitis C Virus Replicon Expression

Department of Pediatrics, Division of Allergy and Immunology, The Children's Hospital of Philadelphia, and the Department of Psychiatry, University of Pennsylvania School of Medicine, 34th St. and Civic Center Blvd., Philadelphia, PA 19104, USA.
American Journal Of Pathology (Impact Factor: 4.59). 12/2005; 167(5):1333-40. DOI: 10.1016/S0002-9440(10)61220-5
Source: PubMed


We previously demonstrated that morphine enhances hepatitis C virus (HCV) replication in human hepatic cells. Here we describe the impact of morphine withdrawal (MW), a recurrent event during the course of opioid abuse, on HCV replicon expression in human hepatic cells. MW enhanced both viral RNA and protein expression in HCV replicon cells. Blocking opioid receptors by treatment with naloxone after morphine cessation (precipitated withdrawal, PW) induced greater HCV replicon expression than MW. Investigation of the mechanism responsible for MW- or PW-mediated HCV enhancement showed that both MW and PW inhibited the expression of endogenous interferon-alpha (IFN-alpha) in the hepatic cells. This down-regulation of intracellular IFN-alpha expression was due to the negative impact of MW or PW on IFN-alpha promoter activation and on the expression of IFN regulatory factor 7 (IRF-7), a strong transactivator of the IFN-alpha promoter. In addition, both MW and PW inhibited the anti-HCV ability of recombinant IFN-alpha in the hepatic cells. These in vitro observations support the concept that opioid abuse favors HCV persistence in hepatic cells by suppressing IFN-alpha-mediated intracellular innate immunity and contributes to the development of chronic HCV infection.

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    • "Given the fact that miRNAs are involved in important biological processes and innate immunity against viral infections , including HCV (Xu et al. 2011; Ding et al. 2012; Kawano et al. 2013), it is of significance to determine whether environmental factors such as heroin abuse, a common practice among IDUs, can dysregulate both cellular and cell-free miRNAs. Although it is known that opiates impair host immunity and enhance HCV replication in vitro (Li et al. 2003; Wang et al. 2005), there is little information about the in vivo impact of heroin on the expression of miRNAs related to innate immunity and HCV infection. "
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    ABSTRACT: Hepatitis C virus (HCV) infection is common among injection drug users (IDUs). There is accumulating evidence that circulating microRNAs (miRNAs) are associated with HCV infection and disease progression. The present study was undertaken to determine the in vivo impact of heroin use on HCV infection and HCV-related circulating miRNA expression. Using the blood specimens from four groups of the study subjects (HCV-infected individuals, heroin users with/without HCV infection, and healthy volunteers), we found that HCV-infected heroin users had significantly higher viral load than HCV-infected non-heroin users (p = 0.0004). Measurement of HCV-related circulating miRNAs in plasma showed that miRs-122, 141, 29a, 29b, and 29c were significantly increased in the heroin users with HCV infection, whereas miR-351, an HCV inhibitory miRNA, was significantly decreased in heroin users as compared to control subjects. Further investigation identified a negative correlation between the plasma levels of miR-29 family members and severity of HCV infection based on aspartate aminotransferase to platelet ratio index (APRI). In addition, heroin use and/or HCV infection also dysregulated a panel of plasma miRNAs. Taken together, these data for the first time revealed in vivo evidence that heroin use and/or HCV infection alter circulating miRNAs, which provides a novel mechanism for the impaired innate anti-HCV immunity among IDUs.
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    • "While both IRF-3 and IRF-7 are the primary players in the activation of IFN-β and IFN-α, respectively, IRF-5 was also characterized as an important factor participating in the induction of IFN-α/β (Barnes et al., 2001). In contrast to our earlier study showing that morphine withdrawal inhibited IRF-5 and IRF-7 expression in human hepatocytes (Li et al., 2007; Wang et al., 2005), we observed that morphine had little effect on the expression of these IRF family members in the neuronal cells (data not shown). This discrepancy could be due to the difference in the cell types used in our earlier work and the present study. "
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    ABSTRACT: Interferon alpha (IFN-alpha) not only plays a key role in innate host immunity against infections but also is involved in the cellular functions of the central nervous system (CNS). In this study, we examined the impact of morphine on IFN-alpha expression in human neuronal cells (NT2-N). Similar to human immune cells, NT2-N cells also expressed IFN-alpha at both mRNA and protein levels. IFN-alpha expression in NT2-N cells, however, was inhibited by morphine. Naltrexone antagonized the inhibitory effect of morphine on IFN-alpha expression in NT2-N cells. The specific mu opioid receptor antagonist, Cys2, Tyr3, Arg5, Pen7-amide (CTAP), also blocked the morphine action on intracellular IFN-alpha expression. Investigation of the mechanisms involved in the morphine action showed that although morphine had little effect on the expression of key IFN regulatory factors (IRFs), morphine inhibited IFN-alpha promoter activation and suppressed the expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1) in the neuronal cells. These findings provide direct in vitro evidence that opioids may impair neuronal cell-mediated innate protection in the CNS.
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    Preview · Article · Dec 2005 · American Journal Of Pathology
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