Abstract
Opioid abuse alters the functions of immune cells in both in vitro and in vivo systems, including macrophages. Here, we investigated the effects of methadone, a widely used opioid receptor agonist for treatment of opiate addiction, on the expression of intracellular viral restriction factors and HIV replication in primary human macrophages. We showed that methadone enhanced the HIV infectivity in primary human macrophages. Mechanistically, methadone treatment of macrophages reduced the expression of interferons (IFN-β and IFN-λ2) and the IFN-stimulated anti-HIV genes (APOBEC3F/G and MxB). In addition, methadone-treated macrophages showed lower levels of several anti-HIV microRNAs (miRNA-28, miR-125b, miR-150, and miR-155) compared to untreated cells. Exogenous IFN-β treatment restored the methadone-induced reduction in the expression of the above genes. These effects of methadone on HIV and the antiviral factors were antagonized by pretreatment of cells with naltrexone. These findings provide additional evidence to support further studies on the role of opiates, including methadone, in the immunopathogenesis of HIV disease.
Highlights
Injection drug use (IDU) is known as a major risk factor for spreading HIV infection and is a global public health concern [1]
Opioid abusers receiving maintenance treatment (MMT) have better adherence to antiretroviral therapy (ART) and lower likelihood of HIV infection associated with drug injection compared to nonMMT treated group [11,12,13, 43]
Previous research indicated that illicit drugs, even alcohol, influenced HIV entry, activated the transcription of HIV LTR, and disordered innate immunity, thereby promoting HIV replication in human immune cells [44,45,46,47,48,49,50,51]
Summary
Injection drug use (IDU) is known as a major risk factor for spreading HIV infection and is a global public health concern [1]. High and sustained levels of medication adherence are required for the effectiveness treatment, which can be challenging for HIV patients [6, 7]. MMT decreases illicit opioid use and reduces HIV acquisition but is critical to improving the medication. Methadone Enhances HIV Infection adherence to ART [14]. Several studies have reported that opioids enhance HIV infection through several mechanisms, including upregulation of HIV coreceptors (CCR5 and CXCR4) [18], inflammatory cytokines [19, 20], inhibition of IFNs, and IFN stimulating genes [21, 22]. We initiated this study to explore the impact of methadone on the intracellular immunity and HIV infection of primary human macrophages
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