Morphine and gp120 Toxic Interactions in Striatal Neurons are Dependent on HIV-1 Strain

Podhaizer, Elizabeth M.; Zou, Shiping; Fitting, Sylvia; Samano, Kimberly L.; El‐Hage, Nazira; Knapp, Pamela E.; Hauser, Kurt F.

doi:10.1007/s11481-011-9326-z

Cited by 47 publications

(64 citation statements)

References 125 publications

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“…Our studies conclusively show that opiates can directly exacerbate the deleterious effects of HIV-1 on neurons in an infective model in vitro , although past studies have demonstrated that morphine interacts with the HIV-1 proteins Tat [21], [23] and gp120 [24]. The present studies also confirm and extend prior findings of glial involvement in interactions between opiates and HIV proteins, demonstrating that combined morphine and HIV-1 SF162 neurotoxicity can be amplified in the presence of glia.…”

Section: Discussionsupporting

confidence: 85%

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Morphine Enhances HIV-1SF162-Mediated Neuron Death and Delays Recovery of Injured Neurites

et al. 2014

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HIV-1 enters the CNS soon after initial systemic infection; within the CNS parenchyma infected and/or activated perivascular macrophages, microglia and astrocytes release viral and cellular toxins that drive secondary toxicity in neurons and other cell types. Our previous work has largely modeled HIV-neuropathology using the individual viral proteins Tat or gp120, with murine striatal neurons as targets. To model disease processes more closely, the current study uses supernatant from HIV-1-infected cells. Supernatant from HIV-1SF162-infected differentiated-U937 cells (HIV+ sup) was collected and p24 level was measured by ELISA to assess the infection. Injection drug abuse is a significant risk factor for HIV-infection, and opiate drug abusers show increased HIV-neuropathology, even with anti-retroviral treatments. We therefore assessed HIV+ sup effects on neuronal survival and neurite growth/pruning with or without concurrent exposure to morphine, an opiate that preferentially acts through µ-opioid receptors. Effects of HIV+ sup ± morphine were assessed on neuronal populations, and also by time-lapse imaging of individual cells. HIV+ sup caused dose-dependent toxicity over a range of p24 levels (10–500 pg/ml). Significant interactions occurred with morphine at lower p24 levels (10 and 25 pg/ml), and GSK3β was implicated as a point of convergence. In the presence of glia, selective neurotoxic measures were significantly enhanced and interactions with morphine were also augmented, perhaps related to a decreased level of BDNF. Importantly, the arrest of neurite growth that occurred with exposure to HIV+ sup was reversible unless neurons were continuously exposed to morphine. Thus, while reducing HIV-infection levels may be protective, ongoing exposure to opiates may limit recovery. Opiate interactions observed in this HIV-infective environment were similar, though not entirely concordant, with Tat/gp120 interactions reported previously, suggesting unique interactions with virions or other viral or cellular proteins released by infected and/or activated cells.

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Section: Discussionsupporting

confidence: 85%

“…Opiate drugs of abuse have been shown to enhance particular damaging effects of HIV-1 proteins in vitro [21]–[24], [72]. However, the CNS of HIV-1-infected patients is exposed to a great many other cellular and viral factors released from infected and/or activated cells.…”

Section: Discussionmentioning

confidence: 99%

Morphine Enhances HIV-1SF162-Mediated Neuron Death and Delays Recovery of Injured Neurites

et al. 2014

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“…This notion is in consistence with previous studies that virus, Tat and gp120 may directly contribute to HAND (Paris et al 2015;Podhaizer et al 2012;Zou et al 2007). Because gp120 glycoproteins can be taken up by brain microvessels and transported across the BBB (Banks et al 2005), it is possible that higher brain P24 antgenemia in HIV-1 JR-FL -infected mice contribute to severer neuron damages as compared with HIV-1 BJZS7 -infected animals.…”

Section: Discussionsupporting

confidence: 81%

“…Because gp120 glycoproteins can be taken up by brain microvessels and transported across the BBB (Banks et al 2005), it is possible that higher brain P24 antgenemia in HIV-1 JR-FL -infected mice contribute to severer neuron damages as compared with HIV-1 BJZS7 -infected animals. However we cannot exclude the possibility that HIV-1 strain-specific differences in Tat and gp120 may also determine the neurotoxicity (Podhaizer et al 2012). To this end, more T/F viruses should be tested in future studies.…”

Section: Discussionmentioning

confidence: 94%

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

Liu

Cheung

et al. 2016

J Neuroimmune Pharmacol

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Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is one of the common causes of cognitive dysfunction and morbidity among infected patients. However, to date, it remains unknown if a transmitted/founder (T/F) HIV-1 leads to neurological disorders during acute phase of infection. Since it is impossible to answer this question in humans, we studied NOD.Cg-Prkdc scid Il2rgtm1Wjl/SzJ mice (NSG) reconstituted with human PBMC (NSG-HuPBL), followed by the peritoneal challenge with the chronic HIV-1JR-FL and the T/F HIV-1BJZS7, respectively. By measuring viral load, P24 antigenemia and P24(+) cells in peripheral blood and various tissue compartments, we found that systemic infections were rapidly established in NSG-HuPBL mice by both HIV-1 strains. Although comparable peripheral viral loads were detected during acute infection, the T/F virus appeared to cause less CD4(+) T cell loss and less numbers of infected cells in different organs and tissue compartments. Both viruses, however, invaded brains with P24(+)/CD3(+) T cells detected primarily in meninges, cerebral cortex and perivascular areas. Critically, brain infections with HIV-1JR-FL but not with HIV-1BJZS7 resulted in damaged neurons together with activated microgliosis and astrocytosis as determined by significantly increased numbers of Iba1(+) microglial cells and GFAP(+) astrocytes, respectively. The increased Iba1(+) microglia was correlated positively with levels of P24 antigenemia and negatively with numbers of NeuN(+) neurons in brains of infected animals. Our findings, therefore, indicate the establishment of two useful NSG-HuPBL models, which may facilitate future investigation of mechanisms underlying HIV-1-induced microgliosis and astrocytosis.

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“…57 The activated macrophages and microglia begin to release inflammatory cytokines (for example, TNFa), chemokines and other neurotoxins 54,55 to enhance the neuropathy.…”

Section: Discussionmentioning

confidence: 99%

HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

et al. 2014

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Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite extensive research, the detailed neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. In this study, we investigated the role of proinflammatory molecules, tumor necrosis factor-α (TNFα), CXCR4 and stromal-derived factor-1 α (SDF1α), in the L4/5 dorsal root ganglia (DRG) and the spinal dorsal horn in HIV gp120 protein-mediated neuropathic pain. Our results showed that the application of HIV gp120 to the sciatic nerve induced upregulation of TNFα, CXCR4 and SDF1α in both the DRG and the lumbar spinal dorsal horn. Non-replicating herpes simplex virus (HSV) vector encoding the p55TNFSR gene and producing a TNF-soluble receptor (TNFSR) to block bioactivity of TNFα reversed mechanical allodynia. Intrathecal AMD3100 (CXCR4 antagonist) increased mechanical threshold. The HSV vectors expressing p55TNFSR reversed upregulation of TNFα, CXCR4 and SDF1α induced by gp120 in the DRG and the spinal dorsal horn. These studies suggest that proinflammatory TNFα to the CXCR4/SDF1 pathway has an important role in the HIV-related neuropathic pain state and that blocking the proinflammatory cytokines or chemokines is able to reduce neuropathic pain. This work provides a novel gene therapy proof-of-concept for HIV-associated neuropathic pain.

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Morphine and gp120 Toxic Interactions in Striatal Neurons are Dependent on HIV-1 Strain

Cited by 47 publications

References 125 publications

Morphine Enhances HIV-1SF162-Mediated Neuron Death and Delays Recovery of Injured Neurites

Morphine Enhances HIV-1SF162-Mediated Neuron Death and Delays Recovery of Injured Neurites

Brain Invasion by CD4+ T Cells Infected with a Transmitted/Founder HIV-1BJZS7 During Acute Stage in Humanized Mice

HSV-mediated p55TNFSR reduces neuropathic pain induced by HIV gp120 in rats through CXCR4 activity

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