Research Article: Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder

Date Published: May 20, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Pichili Vijaya Bhaskar Reddy, Sudheesh Pilakka-Kanthikeel, Shailendra K. Saxena, Zainulabedin Saiyed, Madhavan P. N. Nair.

http://doi.org/10.1155/2012/953678

Abstract

HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population.

Partial Text

The HIV epidemic continues to be the most severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV.During the later stages of the disease, HIV-1-infected patients suffer from a wide range of neurological and neurocognitive disorders collectively known as HIV-associated neurocognitive disorder (HAND) [1–6]). Severe neuropathological changes resulting in significantly higher neurocognitive dysfunctions have been linked with other infections or illicit drug abuse. According to recent studies, it is believed that illicit drug abuse is one of the leading causes for transmission of HIV within USA [7–13]. Injection drug users are at a higher risk of getting infected with HIV and have greater chances of developing neurological abnormalities and other opportunistic infections as a result of sharing contaminated needles and increased risky sexual behavior [14–16]. Combined HIV infection along with opiate drug addiction has gained attention in the recent years and is an emerging problem in the post-HAART era since these individuals live longer; however, the associated neurological abnormalities remain among most of the clinical disorders observed in HIV-infected patients [8–10, 12, 17, 18].

Chronic abuse of opiate drugs significantly increases the viral titers and affects the CD4 T cells in HIV-infected subjects [27, 28]. Apoptosis has been postulated to be a cause for the significant loss of T cells, thereby worsening the clinical condition of HIV-infected patients. HIV virus and many of the proteins that are encoded by HIV genome including gp120, Tat, Nef, Vpr, Vpu, and HIV protease have been found to have pro- and/or antiapoptotic qualities [29–32]. Peterson and colleagues have shown that morphine increases HIV-1 replication in human peripheral blood mononuclear cells (PBMCs) that are chronically infected with HIV [33, 34]. Our studies for the first time have indicated that PBMCs treated with morphine induce significant apoptosis (Figure 1). Cells treated with morphine showed evident DNA fragmentation as compared to their respective controls. Our studies in total suggested that morphine can cause immunosuppression during HIV infection possibly by inducing apoptosis either independently or by acting as a cofactor in the pathogenesis of HIV infection [35]. In another study, Moorman et al. [36] reported that freshly isolated human PBMCs when infected with either HIV-1 gp120/anti-gp120 or morphine (3 μM) alone did not cause a significant apoptosis. However, a combined infection with HIV-1 gp120/anti-gp120 in the presence of morphine significantly enhanced the percentage of apoptotic cells. Opiate drugs bind to μ opioid receptors present on different kinds of immune cells and thus affect the inflammatory responses including macrophage modulation and production of different kinds of cytokines [33, 37, 38]. Upregulation of μ opioid receptor has been suggested to play an important role in HIV infection [39]. In correlation with these results, studies of Moorman et al. have demonstrated that mice lacking μ opioid receptors showed significantly lowered apoptosis as compared to wild types when treated with HIV-1 gp120 and morphine [36].

HIV is known to infect various CNS cells like microglia, astrocytes and cause neuronal dysfunction leading to dementia. Astrocytes represent a major population of nonneuronal cells in the brain that comprise about 25–50% of the total volume of the brain. Several studies have shown the important role played by astrocytes in supporting the neurons and their function. Although astrocytes have been shown to play a vital role in the neuropathogenesis of HIV, astrocytes are not productively infected with HIV unlike other cells such as macrophages, microglia, and monocytes.

Chemokines have taken a central focus in the recent years mainly due to the fact that they possess inhibitory effects on HIV infection [62, 63]. Chemokines represent small proteins of 5–12 kDA in size that are known to act as chemoattractants for NK cells, T cells, monocytes, neutrophils, fibroblasts, and endothelial cells. They are important mediators of transmigration of leucocytes across the BBB and play a significant role in the neuropathogenesis of HAND since these molecules recruit and regulate the movement of inflammatory cells into the CNS. Further, chemokines also regulate the degree of HIV infection [64, 65]. Deregulation in chemokine expression is a common phenomenon that is associated with astrocytes, microglia, macrophages, neurons, and endothelial cells exposed to virus, viral proteins and also in HIV dementia patients [66–69]. MIP-1β, also known as macrophage inflammatory protein has been reported to block CCR5 and CCR3 receptors [58, 70, 71]. Studies from our laboratory have shown that astrocytes treated with morphine at concentrations 10−7 M, 10−9 M, 10−11 M for a period of 48 h significantly inhibited the protective gene MIP-1β expression by 78%, 65%, and 43%, respectively [49]. Monocyte chemoattractant protein (MCP)-1 is another CC-chemokine ligand (CCL2) that is particularly important in HIV neuropathogenesis in part because it mediates mononuclear phagocytes and leukocytes migration into the brain [66, 67]. Lines of evidence have indicated that the levels of CCL2 (MCP-1) and the CCR2 receptor levels very well correlate with the neurocognitive defects accompanying the neuropathogenesis of HIV disease progression [72, 73]. Earlier studies have shown that exposure of astrocytes with HIV-Tat and morphine together result in a synergistic increase in the release of the CCL2; however such synergism was lacking in the microglial cells [59]. Constitutively expressed CCL2 mRNA was significantly upregulated in human neurons by morphine exposure in a concentration and time-dependent manner but not in human astrocytes and microglia cells even though microglia and astrocytes also constitutively express CCL2 [74]. A μ opioid receptor agonist [D-Ala2, N-Me-Phe4, Glyol5] enkephalin (DAMGO) was shown to increase the expression of proinflammatory chemokines like CCL2, CCL5, and CXCL10 in PHA-stimulated human PBMCs at both protein and mRNA levels [75]. Increased CCL2 in astrocytes near the area of HIV Tat injection following the systemic administration of morphine indicates the role of morphine in enhancing inflammatory responses [48]. Consistent with these reports, it has been shown that glial activation and inflammation was attenuated completely in the CCR2 knockout mice compared to the wild type after the Tat and morphine injection either alone or together [76]. In addition to CCL2, CCL5, and CCL3 (MIP-1α) protein and mRNA expression levels were significantly exacerbated when exposed to Tat and morphine together as compared to either of them when present alone. Further these studies indicated that the ability of morphine to enhance the Tat-induced chemokine production is mediated by μ opioid receptors [59].

Infection of cells with HIV requires the presence of coreceptors like CCR5, CCR2b, and CCR3 in addition to CD4+ receptors [58, 70]. These coreceptors are located in various cell types including brain cells [77]. It is possible that chemokines bind to more than one specific receptor. Mip-1β binds to CCR5 and CCR3 while MCP-1 binds to the CCR2b receptor. Both chemokines and their receptors have been demonstrated to play important roles in the neuropathogenesis of HIV infection. These receptors have also been shown to be present in higher levels in autopsied brain samples obtained from AIDS patients and have been shown to act as coreceptors for HIV infection [78–83].

Changes in the expression of chemokines and their receptors can lead to signaling events that regulate various biological responses such as increased calcium influx and mitogen-activated protein kinase (MAPK) activation. Endogenous opioid peptides and agonists of opioid drugs have the potential to activate various signaling cascades either by suppressing adenyl cyclase, cation channels, or MAPK pathways [91]. Studies from our laboratory have shown that morphine increases p38 MAPK and down-regulates cAMP response element binding (CREB) gene and protein expression in U87 astrocytes [49] (Figures 3(b) and 3(c)). Consistent with these studies, other investigators have identified the involvement of various mitogen-activated kinases in morphine-mediated toxicity [92, 93]. Stimulation of MAPKs has been shown to regulate the HIV-1 infectivity [94–96]. Binding of morphine to the μ opioid receptor stimulates G-protein-associated molecules thereby inhibiting cAMP and resulting in lowered phosphorylation of CREB [91]. CREB mediated transcription is an important factor in neuronal adaptive response and has been demonstrated to be vital for normal neurocognitive functioning [97–99]. Increased phosphorylation of ERK1/2, JNK, p38, and Akt in a time-dependent manner has been reported in human brain microvascular endothelial cells when exposed to morphine [100]. In another study using human neurons, Malik et al. showed that the synergistic effects of HIV Tat and morphine involve JNK and ERK1/2 pathways; however, there were no changes in the p38 activation [44]. Chronic treatment of activated T cells with morphine inhibited the phosphorylation and activation of ERK1/2 and p38 MAPK further leading to a downregulation of the transcription factors activator protein-1 (AP-1), nuclear factor of activated cells (NFAT) and NFκB [101].

These studies suggest that the drugs of abuse such as morphine enhance HIV-1 replication and infectivity in various cell types such as PBMCs and CNS cells. The mechanisms involved in such effects may be mediated by altering HIV-1 coreceptors and chemokines. The ability of opioids to alter the expression of chemokines and chemokine receptors by various cells of the central nervous system may significantly enhance the ability of HIV to infect the brain. Morphine also alters the status of both pro- and antiapoptotic molecules finally leading to a higher rate of apoptosis which is further exacerbated in case of HIV infection and such events are mediated by various signaling mechanisms. Overall, HIV infection in the brain may be enhanced either by viral binding and cellular uptake by upregulating HIV coreceptors or chemokine expression. Together, these studies provide important information on the molecular aspects of morphine, HIV-1 infection, and HIV pathogenesis, which may help in developing novel anti-HIV strategies targeting the coreceptors and chemokines.

 

Source:

http://doi.org/10.1155/2012/953678

 

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