Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis

Abstract

About one third of acquired immunodeficiency syndrome cases in the USA have been attributed to the use of injected addictive drugs, frequently involving opioids like heroin and morphine, establishing them as significant predisposing risk factors for contracting human immunodeficiency virus type 1 (HIV-1). Accumulating evidence from in vitro and in vivo experimental systems indicates that opioids act in concert with HIV-1 proteins to exacerbate dysregulation of neural and immune cell function and survival through diverse molecular mechanisms. In contrast, the impact of opioid exposure and withdrawal on the viral life cycle and HIV-1 disease progression itself is unclear, with conflicting reports emerging from the simian immunodeficiency virus and simian-human immunodeficiency virus infection models. However, these studies suggest a potential role of opioids in elevated viral production. Because human microglia, astrocytes, CD4+ T lymphocytes, and monocyte-derived macrophages express opioid receptors, it is likely that intracellular signaling events triggered by morphine facilitate enhancement of HIV-1 infection in these target cell populations. This review highlights the biochemical changes that accompany prolonged exposure to and withdrawal from morphine that synergize with HIV-1 proteins to disrupt normal cellular physiological functions especially within the central nervous system. More importantly, it collates evidence from epidemiological studies, animal models, and heterologous cell systems to propose a mechanistic link between such physiological adaptations and direct modulation of HIV-1 production. Understanding the opioid-HIV-1 interface at the molecular level is vitally important in designing better treatment strategies for HIV-1-infected patients who abuse opioids.

Fig. 1

Hypothetical model for Gα_i/o-coupled receptor-induced heterologous sensitization. Whereas acute activation of Gα_i/o-coupled opioid receptors leads to inhibition of cAMP accumulation, prolonged (chronic) activation enhances adenyl cyclase-mediated cAMP response when the opioid agonist is removed. The supersensitivity of adenyl cyclase, also termed heterologous sensitization, manifests itself as cAMP overproduction. AC adenyl cyclase, AW abrupt withdrawal, PW precipitated withdrawal

Fig. 2

Morphine signaling in an HIV-1-infected CNS resident cell alters the transcriptional profile of the cell and enhances neurotoxicity. a Acute exposure of an infected perivascular macrophage or microglial cell within the CNS to morphine will activate the receptor-coupled Gα_i subunit leading to inhibition of adenyl cyclase (AC) and decreased levels of cAMP. However, under prolonged exposure, a Gα_s subunit associates with the μ-opioid receptor (MOR) and becomes activated, activates AC, and increases levels of cAMP. Protein kinase A (PKA) exists in the cytoplasm in an inactive form as two regulatory (R) subunits associated with two catalytic (C) subunits. Binding of cAMP to the R subunits causes activation and dissociation of the C subunits, which can then enter the nucleus where they can phosphorylate the transcription factor cAMP response element binding (CREB) protein, and the now active CREB binds cAMP response element (CRE) sequences within the promoter region of the target genes. These target genes include the HIV-1 LTR, leading to increased viral transcription, as well as the HIV-1 coreceptors CXCR4 and CCR5, leading to increased expression of the receptors on the cell surface, potentially enhancing infection by HIV-1. Cytoplasmic Ca²⁺ levels also increase. Increased viral synthesis; increased production and secretion of the viral proteins gp120 and Tat along with host proteins RANTES, MCP-1,5, IL-1β, IL-6, and TNF-α; and increased levels of glutamate and aspartate in the CSF impact surrounding neurons. In addition, morphine can act synergistically with these viral proteins to further increase these signaling cascades. b High levels of Tat, gp120, IL-1β, IL-6, and TNF-α lead to the phosphorylation and activation of p38/MAPK, triggering a signaling cascade resulting in apoptosis of the neuron. The increased presence of aspartate and glutamate can lead to excitotoxicity through increased binding of either amino acid to the N-methyl-D-aspartic acid receptor (NMDAR), causing an influx of Ca²⁺, which can either trigger an independent apoptotic cascade or enhance activation of p38/MAPK, also resulting in neuronal apoptosis. Direct exposure of neurons to morphine causes an increase in cleaved, active caspase-3 and an increase in ferritin heavy chain protein (FHC), which can inhibit the prosurvival signaling cascade triggered by SDF-1 binding CXCR4, both of which may contribute to neuronal cell death