Morphine Suppresses IFN Signaling Pathway and Enhances AIDS Virus Infection

Abstract

BackgroundOpioids exert a profound influence on immunomodulation and enhance HIV infection and replication. However, the mechanism(s) of their action remains to be determined. We thus investigated the impact of morphine on the intracellular innate antiviral immunity.Methodology/Principal FindingsSeven-day-cultured macrophages were infected with equal amounts of cell-free HIV Bal or SIV DeltaB670 for 2 h at 37°C after 24 h of treatment with or without morphine. Effect of morphine on HIV/SIV infection and replication was evaluated by HIV/SIV RT activity assay and indirect immunofluorescence for HIV p24 or SIV p28 antigen. The mRNA expression of cellular factors suppressed or induced by morphine treatment was analyzed by the real-time RT-PCR. We demonstrated that morphine treatment of human blood monocyte-derived macrophages significantly inhibited the expression of interferons (IFN-α, IFN-β and IFN-λ) and IFN-inducible genes (APOBEC3C/3F/3G and 3H). The further experiments showed that morphine suppressed the expression of several key elements (RIG-I and IRF-7) in IFN signaling pathway. In addition, morphine treatment induced the expression of suppressor of cytokine signaling protein-1, 2, 3 (SOCS-1, 2, 3) and protein inhibitors of activated STAT-1, 3, X, Y (PIAS-1, 3, X, Y), the key negative regulators of IFN signaling pathway.ConclusionsThese findings indicate that morphine impairs intracellular innate antiviral mechanism(s) in macrophages, contributing to cell susceptibility to AIDS virus infection.

Neuronal Stress and Injury Caused by HIV-1, cART and Drug Abuse: Converging Contributions to HAND

“…Studying the combination of HIV and_cART with other abused drugs, such as heroin and cocaine, seems equally important as these substances may involve other pathways and affect HIV neuropathogenesis in different ways than METH [15,16,17,18,240]. Moreover, we largely focused on neuronal injury, but METH as well as other abused drugs also affect the immune system and HIV infection itself by compromising for example the interferon response [241,242,243,244]. Opioids, cocaine and METH are highly addictive and all seem to be able to influence gene expression in neural and immune cells via mechanisms that involve short, con-coding, regulatory microRNAs and compromise control of HIV infection as well as normal neuronal function [19,245].…”

IL-4, JAK-STAT signaling, and pain

“…Conclusively, the authors also found reduced expression of JAK-STAT-induced cytokines (IFN-α, IFN-β, and IFN-γ) and of IFN-inducible genes. 80 These findings may spawn new therapeutic interventions using morphine and other opioids.…”

Opiate use inhibits TLR9 signaling pathway in vivo: possible role in pathogenesis of HIV-1 infection

“…One possible reason for this discrepancy is that the effects of the morphine derivative on HIV production may be different than those from morphine. Importantly, several other studies have confirmed that morphine enhances HIV infection in several peripheral blood mononuclear cells (PBMCs), such as macrophages and CD4 + T cells 18,19 . Therefore, the molecular mechanism of opiate use in the pathogenesis of HIV-1 infection is not fully understood.…”