Abstract
The US is in the midst of a major drug epidemic fueled in large part by the widespread recreational use of synthetic opioids such as fentanyl. Persons with opioid use disorder are at significant risk for transmission of injection-associated infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV). Commonly abused substances may antagonize immune responses and promote viral replication. However, the impact of synthetic opioids on virus replication has not been well explored. Thus, we evaluated the impact of fentanyl and carfentanil using in vitro systems that replicate infectious viruses. Fentanyl was used in cell lines replicating HBV or HCV at concentrations of 1 ng, 100 ng, and 10 ug. Viral protein synthesis was quantified by ELISA, while apoptosis and cell death were measured by M30 or MTT assays, respectively. HCV replicative fitness was evaluated in a luciferase-based system. RNAseq was performed to evaluate cellular gene regulation in the presence of fentanyl. Low dose fentanyl had no impact on HCV replication in Huh7.5JFH1 hepatocytes; however, higher doses significantly enhanced HCV replication. Similarly, a dose-dependent increase in HCV replicative fitness was observed in the presence of fentanyl. In the HepG2.2.15 hepatocyte cell line, fentanyl caused a dose-dependent increase in HBV replication, although only a higher doses than for HCV. Addition of fentanyl resulted in significant apoptosis in both hepatocyte cell lines. Cell death was minimal at low drug concentrations. RNAseq identified a number of hepatocyte genes that were differentially regulated by fentanyl, including those related to apoptosis, the antiviral / interferon response, chemokine signaling, and NFκB signaling. Collectively, these data suggest that synthetic opioids promote viral replication but may have distinct effects depending on the drug dose and the viral target. As higher viral loads are associated with pathogenesis and virus transmission, additional research is essential to an enhanced understanding of opioid-virus pathogenesis and for the development of new and optimized treatment strategies.
Highlights
The US is experience a major opioid crisis [1], and the harmful effects of opioid use disorder (OUD) continue unabated despite the availability of harm reduction and prevention strategies
Because a robust understanding of opioid-host and opioid-virus interactions is essential for the development of new and optimized treatment and harm reduction strategies, we evaluated the impact of fentanyl on hepatic viral replication in vitro
Mu opioid receptor expression was quantified by ELISA in several hepatocyte-derived cell lines, including Huh7.5JFH1 (HCV-infected), the parental / uninfected Huh7.5, and HepG2.2.15 (HBV-infected)
Summary
The US is experience a major opioid crisis [1], and the harmful effects of opioid use disorder (OUD) continue unabated despite the availability of harm reduction and prevention strategies. Recent data demonstrate that approximately 90% of unintentional overdoses involved fentanyl or fentanyl analogs [3,4,5,6] Opioids comprise both endogenous and exogenous or synthetic compounds that function by activating several opioid receptors. Opioid receptors are expressed on a variety of immune cells including lymphocytes, monocytes, macrophages, and neutrophils [7,8,9] They are expressed in the liver–including in hepatocytes and hepatic stellate cells–and are important mediators of liver disease progression [10,11,12,13,14,15,16]. Because a robust understanding of opioid-host and opioid-virus interactions is essential for the development of new and optimized treatment and harm reduction strategies, we evaluated the impact of fentanyl on hepatic viral replication in vitro
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