Dataset Information

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.

SUBMITTER: Madhuravasal Krishnan J

PROVIDER: S-EPMC10145664 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Madhuravasal Krishnan Janani J Kong Ling L Karns Rebekah R Medvedovic Mario M Sherman Kenneth E KE Blackard Jason T JT

Viruses 20230421 4

<h4>Background</h4>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.<h4>Methods</h4>TZM-bl and HIV-infected lymphocyte cells were incubated with fentanyl at varying concentrations. Expression ...[more]

PMID: 37113007

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Project description:BackgroundThe illicit use of synthetic opioids such as fentanyl has led to a serious public health crisis in the US. People with opioid use disorder are more likely to contract infections such as HIV and viral hepatitis and experience more severe disease. While several drugs of abuse are known to enhance viral replication and suppress immunologic responses, the effects of synthetic opioids on HIV pathogenesis have not been investigated thoroughly. Thus, we examined the impact of fentanyl on HIV replication and chemokine receptor expression in the U937 cell line and monocyte-derived macrophages (MDMs).MethodsU937 cells were exposed to varying concentrations of fentanyl. Expression levels of the CXCR4 and CCR5 chemokine receptors were measured in cell lysates. HIV p24 antigen was quantified in culture supernatants by ELISA, and HIV proviral DNA was quantified in cells using SYBR real-time PCR targeting the pol gene. RNAseq was performed to characterize cellular gene regulation in the presence of fentanyl.ResultsFentanyl induced HIV p24 expression and proviral DNA levels in U937 cells and in primary MDMs. The opioid antagonist naltrexone blocked the effect of fentanyl and reversed the expression of HIV protein and proviral DNA. Fentanyl led to a non-significant decrease in CXCR4 and CCR5 protein levels in U937 cells. RNA sequencing identified several differentially expressed genes in cells infected with HIV and exposed to fentanyl compared to infected cells with no drug exposure. Several microRNAs were also differentially expressed upon fentanyl exposure but not at a statistically significant level.ConclusionThese data demonstrate that the synthetic opioid fentanyl can promote HIV replication in macrophages. As higher HIV levels lead to accelerated disease progression and a higher risk of transmission to others, further research is needed to better understand opioid-virus interactions and to develop new and/or optimized treatment strategies for people living with HIV and opioid use.

Project description: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.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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