title: HIV-1 coinfection and morphine coexposure severely dysregulate hepatitis C virus-induced hepatic proinflammatory cytokine release and free radical production: increased pathogenesis coincides with uncoordinated host defenses.
abstract: Coinfection with human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV) is a global problem that is more prevalent in injection drug users because they have a higher risk for acquiring both viruses. The roles of inflammatory cytokines and oxidative stress were examined in HIV-1- and HCV-coinfected human hepatic cells. Morphine (the bioactive product of heroin), HIV-1 Tat and the MN strain gp120 (gp120(MN)) proteins, and X4 HIV-1(LAI/IIIB) and R5 HIV-1(SF162) isolates were used to study the mechanisms of disease progression in HCV (JFH1)-infected Huh7.5.1 cell populations. HCV increased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release and augmented production of reactive oxygen species (ROS), nitric oxide (NO), and 3-nitrotyrosine (3-NT) in Huh7.5.1 cells. Morphine preferentially affected R5-tropic, but not X4-tropic, HIV-1 interactions with Huh7.5.1 cells. HIV-1 proteins or isolates increased cytokine release in HCV-infected cells, while adding morphine to coinfected cells caused complex imbalances, significantly disrupting cytokine secretion depending on the cytokine, morphine concentration, exposure duration, and particular pathogen involved. Production of ROS, NO, and 3-NT increased significantly in HCV- and HIV-1-coexposed cells while exposure to morphine further increased ROS. The proteasome inhibitor MG132 significantly decreased oxyradicals, cytokine levels, and HCV protein levels. Our findings indicate that hepatic inflammation is increased by combined exposure to HCV and HIV-1, that the ubiquitin-proteasome system and NF-κB contribute to key aspects of the response, and that morphine further exacerbates the disruption of host defenses. The results suggest that opioid abuse and HIV-1 coinfection each further accelerate HCV-mediated liver disease by dysregulating immune defenses.
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, 1217 East Marshall Street, Richmond, VA 23298-0613, USA. nelhage@vcu.edu
authors: Nazira
authors: N
authors: El-Hage
authors: Seth M
authors: SM
authors: Dever
authors: Sylvia
authors: S
authors: Fitting
authors: Tasrif
authors: T
authors: Ahmed
authors: Kurt F
authors: KF
authors: Hauser
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity*; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity*; D006526:Hepatitis C / Q000150:complications / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D006801:Humans; D009020:Morphine / Q000633:toxicity*
chemical_list: D016207:Cytokines; D005609:Free Radicals; D009020:Morphine