Drug abuse, innate immunity and hepatitis C virus.
ABSTRACT Since its discovery in 1989, hepatitis C virus (HCV) has become a major public health problem. HCV chronically infects an estimated 170 million people worldwide. The seroprevalence of anti-HCV antibody in the United States has been estimated at 1.8%, which corresponds to approximately 4 million people. HCV is the most common chronic blood borne infection in the United States, and the leading cause of liver transplantation in developed countries. Injection drug use is the dominant mode of HCV transmission and accounts for up to 90% of current infections. Opiates and other drug abuse, such as alcohol, have been implicated as cofactors in the pathogenesis of HCV disease. Injection drug use has been the most common risk factor identified in alcoholics with HCV infection. Both opiates and alcohol contribute significantly to morbidity and mortality from HCV disease. These drugs most likely act synergistically to promote the development and progression of HCV disease. However, there is limited information available concerning the interaction of the drug abuse with the host cell innate immunity against HCV infection, which is a major barrier to fundamental understanding of the immunopathogenesis of HCV disease. Therefore, defining the role of the drug abuse in the development of chronic HCV infection is of crucial importance and should provide practical guidance toward the reduction of risk factors that interfere with therapeutic approaches for HCV infection and disease. This review paper focuses on the interplay between drug abuse (opiates and alcohol), innate immunity and HCV in the context of the development of HCV disease.
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ABSTRACT: The Independent Scientific Committee on Drugs (ISCD) assigned quantitative scores for harm to 20 drugs. We hypothesized that a personalized, ISCD-based Composite Harm Score (CHS) would be associated with poor health outcomes in polysubstance users. A prospective community sample (n=293) of adults living in marginal housing was assessed for substance use. The CHS was calculated based on the ISCD index, and the personal substance use characteristics over four weeks. Regression models estimated the association between CHS and physical, psychological, and social health outcomes. Polysubstance use was pervasive (95.8%), as was multimorbid illness (median 3, possible range 0-12). The median CHS was 2845 (interquartile range 1865-3977). Adjusting for age and sex, every 1000-unit CHS increase was associated with greater mortality (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.07-2.01, p = 0.02), and persistent hepatitis C infection (OR 1.29, 95% CI 1.02-1.67, p = 0.04). The likelihood of substance-induced psychosis increased 1.39-fold (95% CI 1.13-1.67, p = 0.001). The amount spent on drugs increased 1.51-fold (1.40-1.62, p < 0.001) and the odds of having committed a crime increased 1.74-fold (1.46-2.10, p < 0.001). Multimorbid illness increased 1.43-fold (95% CI 1.26-1.63, p < 0.001). Greater CHS predicts poorer physical, psychological, and social health, and may be a useful quantitative, personalized measure of risk for drug-related harm.PLoS ONE 11/2013; 8(11):e79754. · 3.53 Impact Factor
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ABSTRACT: In Western countries, chronic hepatitis C virus (HCV)-infection mostly affects former and active substance users. The effect of active substance use on interferon (IFN)-responsiveness and therapy efficacy is not well understood. In this study, we compared natural killer (NK) cell activity and function in healthy controls and chronic HCV-infected patients with and without active substance use, as well as the early effects of antiviral therapy with peg-IFN and ribavirin.No differences were observed between chronic HCV patients and healthy individuals in the number and frequencies of CD56dim and CD56bright NK cells. Also, IL-12/18-induced IFN-gamma production by NK cells was comparable between all groups, whereas the cytotoxic ability of NK cells (granzyme and CD107a levels) was more potent in HCV-infected patients as compared to healthy controls, and highest in non-substance users. Moreover, at baseline, the activation of NK cells was significantly lower in HCV-infected patients who used substances, when compared to healthy individuals. Therapy-induced viral load reduction assessed early at day 7 showed a similar decline in substance users and non-substance use HCV patients, with 25% substance users and 17% non-substance users testing HCV-RNA negative at day 7. Furthermore, early during IFN-based therapy, NK cells from HCV patients remained responsive to IFN, and only a minor decline in the degree of STAT-1 phosphorylation was observed irrespective of substance use. These findings were further supported by comparable in vitro p-STAT-1 induction in all three experimental groups.Despite subtle differences at baseline between healthy individuals and chronic HCV patients, we observed that active substance use in chronic HCV-infected patients did not affect the immune responsiveness to IFN early after start of treatment, and thus, we found no evidence – from an immunological point of view – that antiviral therapy of our cohort of HCV-infected patients with active substance use is less efficient.Antiviral research 03/2013; 97(3):347–355. · 3.61 Impact Factor
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ABSTRACT: Opioids exert a profound influence on immunomodulation and enhance HIV infection and replication. However, the mechanism(s) of their action remains to be determined. We thus investigated the impact of morphine on the intracellular innate antiviral immunity. Seven-day-cultured macrophages were infected with equal amounts of cell-free HIV Bal or SIV Delta(B670) for 2 h at 37°C after 24 h of treatment with or without morphine. Effect of morphine on HIV/SIV infection and replication was evaluated by HIV/SIV RT activity assay and indirect immunofluorescence for HIV p24 or SIV p28 antigen. The mRNA expression of cellular factors suppressed or induced by morphine treatment was analyzed by the real-time RT-PCR. We demonstrated that morphine treatment of human blood monocyte-derived macrophages significantly inhibited the expression of interferons (IFN-α, IFN-β and IFN-λ) and IFN-inducible genes (APOBEC3C/3F/3G and 3H). The further experiments showed that morphine suppressed the expression of several key elements (RIG-I and IRF-7) in IFN signaling pathway. In addition, morphine treatment induced the expression of suppressor of cytokine signaling protein-1, 2, 3 (SOCS-1, 2, 3) and protein inhibitors of activated STAT-1, 3, X, Y (PIAS-1, 3, X, Y), the key negative regulators of IFN signaling pathway. These findings indicate that morphine impairs intracellular innate antiviral mechanism(s) in macrophages, contributing to cell susceptibility to AIDS virus infection.PLoS ONE 02/2012; 7(2):e31167. · 3.53 Impact Factor