Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. The paper by Wang et al., “Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression,” appears in the November issue of The American Journal of Pathology and is accompanied by a commentary.
Hepatitis C virus (HCV) is common among intravenous drug users, with 70 to 80% of abusers infected in the United States. This high association has peaked interest in determining the effects of drug abuse, specifically opiates, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.
Dr. Wen-Zhe Ho has been interested in such interplay for some time. His laboratory has previously shown using cell culture that morphine enhances virus replication and inhibits IFN-alpha (a natural anti-viral factor produced by immune, as well as host cells, and the only one approved in recombinant form for treating HCV infection). To further these results, his lab has used a cell model system to determine the consequences of morphine withdrawal, which is a common recurring event in opioid users.
Chuan-Qing Wang and colleagues examined the effects of morphine withdrawal (MW) on HCV-infected cultured liver cells by exposing cells to the drug for four days followed by its removal. They also assessed the effects of using naloxone, to block the opioid receptors, in conjunction with drug removal, i.e. precipitated morphine withdrawal (PW). To measure HCV replication, they used a virus-like “replicon” that mimics the events that occur in liver cells and expression of viral RNA and proteins that HCV uses. Although the replicon does not produce the infectious virus, the HCV replicon system represents the best available system for examining the impact of opiates on HCV at the time of their research study.
Similar to their previous results, the authors found that MW and PW increased levels of HCV replicon RNA and protein expression. In addition, both withdrawal scenarios inhibited IFN-alpha expression in liver cells in the presence or absence of HCV replicon. Since IFN-alpha is a critical self-defense mechanism utilized by liver cells to fight off viral infection, including HIV, this study suggests that morphine withdrawal weakens host cell immunity and provides a favorable environment for HCV growth in the liver.
The authors extended their study by examining the mechanism behind these observations. MW and PW inactivated the IFN-alpha promoter (the switch for making IFN-alpha) by directly inhibiting its activator, interferon regulatory factor-7 (IRF-7), and this effect was more pronounced in HCV replicon-containing cells. Finally, the ability of IFN-alpha treatment to block HCV replicon expression (85%) fell following MW (60%) and PW (50%). This finding, in conjunction with the earlier report by the same group, provides an explanation to the question of why so many HCV-infected patients fail to respond to IFN-alpha treatment.
Although the clinical relevance of this study remains to be determined, these data showing that withdrawal promotes HCV expression by suppressing anti-HCV factor (IFN-alpha) production by liver cells suggests that “opioid abuse may contribute to the chronicity of HCV infection and promote HCV disease progression.” The study also underscores the necessity of future clinical and epidemiological studies to define the role of opiate abuse in promoting HCV disease.
These results suggest that opioid abusers experiencing periods of drug abuse, followed by periods of withdrawal (due to lack of supplies) may lead to immunocompromised liver. These findings further support the need for methadone maintenance treatment as an additional benefit for opioid abusers.
Research was supported by National Institute on Drug Abuse, National Institutes of Health.
This work involved collaborators at Joseph Stokes, Jr. Research Institute at The Children's Hospital of Philadelphia; The Center for Studies of Addiction, University of Pennsylvania School of Medicine; and The Children’s Hospital of Fudan University, Shanghai, China.
Wang C-Q, Li Y, Douglas SD, Wang X, Metzger DS, Zhang T, Ho W-Z: Morphine withdrawal enhances hepatitis C virus (HCV) replicon expression. Am J Pathol 2005, 167:1333-1340
Commentary: Moore K and Dusheiko G: Opiate abuse and viral replication in hepatitis C. Am J Pathol 2005, 167:1189-1191
The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.
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