The Synthetic Opioid Fentanyl Increases HIV Replication and Chemokine Co-Receptor Expression in Lymphocyte Cell Lines

Abstract

Background: In the United States, the illicit use of synthetic opioids such as fentanyl has led to a serious public health crisis. Synthetic opioids are known to enhance viral replication and to suppress immunologic responses, but their effects on HIV pathogenesis remain unclear. Thus, we examined the impact of fentanyl on HIV-susceptible and HIV-infected cell types. Methods: TZM-bl and HIV-infected lymphocyte cells were incubated with fentanyl at varying concentrations. Expression levels of the CXCR4 and CCR5 chemokine receptors and HIV p24 antigen were quantified with ELISA. HIV proviral DNA was quantified using SYBR RT-PCR. Cell viability was detected with the MTT assay. RNAseq was performed to characterize cellular gene regulation in the presence of fentanyl. Results: Fentanyl enhanced expression of both chemokine receptor levels in a dose-dependent manner in HIV-susceptible and infected cell lines. Similarly, fentanyl induced viral expression in HIV-exposed TZM-bl cells and in HIV-infected lymphocyte cell lines. Multiple genes associated with apoptosis, antiviral/interferon response, chemokine signaling, and NFκB signaling were differentially regulated. Conclusions: Synthetic opioid fentanyl impacts HIV replication and chemokine co-receptor expression. Increased virus levels suggest that opioid use may increase the likelihood of transmission and accelerate disease progression.

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs

“…Several studies have reported that specific opioids could enhance HIV infectivity and replication through the upregulation of HIV co-receptors and impairment of intracellular innate antiviral responses [ 11 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. These findings may explain in vivo observations of a higher frequency of HIV founder viruses following intravenous opioid exposure and greater CD4 T-cell loss and viral set-point in macaques infected with the simian immunodeficiency virus (SIV) and undergoing long-term morphine administration [ 11 ].…”

“…Morphine, fentanyl, buprenorphine, and methadone may variably enhance CCR5 and CXCR4 expression in different cell types [ 11 , 32 , 33 , 36 , 37 ]. Methadone might even downregulate the natural chemokine competing for CCR5 (MIP-1b) in macrophages [ 34 ].…”

“…Specifically, fentanyl enhanced the expression of both CXCR4 and CCR5 co-receptors in a dose-dependent manner, induced viral replication and HIV proviral DNA levels, and affected the expression of several miRNAs involved in HIV restriction pathways as well as in HIV-mediated pathogenesis. As early as after 24 h of exposure it was already capable of altering the cellular transcriptome by up- and down-regulation of several genes associated with apoptosis, antiviral/interferon response, chemokine, and NFκB signaling [ 32 ].…”

“…It is essential to conduct studies that closely replicate physiological conditions, including exposure doses, to validate the previous findings using in vivo data. These Very recently, an in vitro study has detailed several µ-opioid receptor-mediated effects of fentanyl upon HIV-susceptible cell lines and infected lymphocytes, including CD4+ T cells from human donors, summarizing most of the previously described mechanisms [32]. Specifically, fentanyl enhanced the expression of both CXCR4 and CCR5 co-receptors in a dose-dependent manner, induced viral replication and HIV proviral DNA levels, and affected the expression of several miRNAs involved in HIV restriction pathways as well as in HIV-mediated pathogenesis.…”