Adenosine Triphosphate Released from HIV-Infected Macrophages Regulates Glutamatergic Tone and Dendritic Spine Density on Neurons

Tovar‐y‐Romo, Luis B.; Kolson, Dennis L.; Bandaru, Veera Venkata Ratnam; Drewes, Julia L.; Graham, David R.; Haughey, Norman J.

doi:10.1007/s11481-013-9471-7

Cited by 25 publications

(19 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our work also concurs with findings from another laboratory demonstrating that P2X receptors mediate increases in neuronal [Ca 2+ ] i and the culling of dendritic spines in rat hippocampal neurons treated with supernatant from HIV infected monocytes (Tovar-y-Romo et al, 2013). Although further work is needed to expand the understanding of the underlying molecular pathways associated with cation-permeable, ligand-gated purinergic receptors, we propose that members of the P2X receptor subfamily may be valuable therapeutic targets for the treatment of neuroAIDS.…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, P2X receptors may affect AMPA and NMDA receptor levels and function (Gordon et al, 2005; Pankratov et al, 2009; Tai et al, 2010; Baxter et al, 2011), which suggests P2X receptors on neurons and glia may be exerting control over [Ca 2+ ] i through both direct and indirect effects. This concept has also recently been alluded to elsewhere in the context of HIV neuroinflammation (Tovar-y-Romo et al, 2013). …”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures

Sorrell

Hauser

2013

J Neuroimmune Pharmacol

View full text Add to dashboard Cite

Emerging evidence suggests that opioid drugs, such as morphine and heroin, can exacerbate neuroAIDS. Microglia are the principal neuroimmune effectors thought to be responsible for neuron damage in HIV-infected individuals, and evidence suggests that opioid drugs acting via μ opioid receptors in microglia aggravate the neuropathophysiological effects of HIV. Key aspects of microglial function are regulated by the P2X family of ATP activated ligand-gated ion channels. In addition, opioid-dependent microglial activation has been reported to be mediated through P2X4 signaling, which prompted us to investigate whether the cation-permeable P2X receptors contribute to the neurotoxic effects of HIV and morphine. To address this question, neuron survival, as well as other endpoints including changes in dendritic length, extracellular ATP levels, and intracellular calcium levels, was assayed in primary neuron-glia co-cultures from mouse striatum. Treatment with TNP-ATP, a non-selective P2X antagonist, prevented the neurotoxic effects of exposure to morphine and/or the HIV Tat, or ATP alone, suggesting P2X receptors mediate the neurotoxic effects of these insults in striatal neurons. Although P2X7, and perhaps P2X1, receptor activation decreases neuron survival, neither P2X1, P2X3, nor P2X7 selective receptor antagonists prevented Tat and/or morphine-induced neurotoxicity. These and other experiments indicate the P2X receptor family contributes to Tat-and morphine- related neuronal injury, and provide circumstantial evidence implicating P2X4 receptors in particular. Our findings reveal that members of the P2X receptor family, especially P2X4, may be novel therapeutic targets for restricting the synaptodendritic injury and neurodegeneration that accompanies neuroAIDS and opiate abuse.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 94%

Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures

Sorrell

Hauser

2013

J Neuroimmune Pharmacol

View full text Add to dashboard Cite

show abstract

“…An emerging literature demonstrates the importance of extracellular ATP purinergic signaling in viral infections, specifically, those caused by HIV-1 (21,22,(31)(32)(33). While limited data on other enveloped viruses exist, it is reported that internalization of pseudotyped HIV was not reduced by purinergic inhibitors (12).…”

Section: Discussionmentioning

confidence: 99%

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Swartz

Esposito

Durham

et al. 2014

J Virol

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 (HIV-1) infection is chronic and presently still incurable. Antiretroviral drugs effectively suppress replication; however, persistent activation of inflammatory pathways remains a key cause of morbidity. Recent studies proposed that purinergic signaling is required for HIV-1 infection. Purinergic receptors are distributed throughout a wide variety of tissue types and detect extracellular ATP as a danger signal released from dying cells. We have explored how these pathways are involved in the transmission of HIV-1 from cell to cell through virological synapses. Infection of CD4 ؉ T lymphocytes with HIV-1 in the presence of an inhibitor of P2X receptors effectively inhibited HIV-1 infection through both cell-free and cellto-cell contact in a dose-dependent manner. Inhibition of direct cell-to-cell infection did not affect the formation of virological synapses or the subsequent cell-to-cell transfer of HIV-1. During both cell-free and cell-to-cell CD4 ؉ T lymphocyte infection, purinergic antagonists blocked infection at the level of viral membrane fusion. During cell-to-cell transmission, we observed CXCR4 colocalization with the newly internalized virus particles within target lymphocytes and found that the purinergic antagonists did not impair the recruitment of the coreceptor CXCR4 to the site of Gag internalization in the target cell. In a screen of a library of purinergic antagonists, we found that the most potent inhibitors of HIV-1 fusion were those that target P2X receptors, while P2Y-selective receptor antagonists or adenosine receptor antagonists were ineffective. Our results suggest that P2X receptors may provide a therapeutic target and that purinergic antagonists may have potent activity against viral infection of CD4 ؉ T lymphocytes by both cell-free and cell-to-cell transmission. IMPORTANCEThis study identifies purinergic antagonists to be potent inhibitors of HIV-1 cell-free and cell-to-cell-mediated infection and provides a stepwise determination of when these compounds inhibit HIV-1 infection. These data provide a rationale for the development of novel antiretroviral therapies that have a dual role in both direct antiviral activity and the reduction of HIV-associated inflammation. Purinergic antagonists are shown here to have equivalent efficacy in inhibiting HIV infection via cell-free and cell-to-cell infection, and it is shown that purinergic receptors could provide an attractive therapeutic anti-HIV target that might avoid resistance by targeting a host signaling pathway that potently regulates HIV infection. The high-throughput screen of HIV-1 fusion inhibitors further defines P2X-selective compounds among the purinergic compounds as being the most potent HIV entry inhibitors. Clinical studies on these drugs for other inflammatory indications suggest that they are safe, and thus, if developed for use as anti-HIV agents, they could reduce both HIV replication and HIV-related inflammation.

show abstract

“…Nowadays, it is widely accepted that neurodegeneration is one of the principal hallmarks of HAND that occurs without neuronal infection. Brain degeneration and consequently neuronal apoptosis is triggered by signaling of viral products such as Tat and gp120 (Kaul and Lipton 1999; Bansal et al 2000; Gurwell et al 2001; Kaul et al 2001; Hisaka et al 2004; Thomas et al 2009; Merino et al 2011; Zhang et al 2011), cytokines and chemokines (Lee et al 2011; Vazquez-Valls et al 2011; Yan et al 2011; Johansson et al 2013; Lombardelli et al 2013), or by toxins produced from infected macrophages including lysosomal protease cathepsin B(Ciborowski and Gendelman 2006; Tian et al 2008; Turchan-Cholewo et al 2009; Sun et al 2010; Luo et al 2010; Rodriguez-Franco et al 2012; Tovar-Y-Romo et al 2013; Malla et al 2014). Furthermore, studies demonstrated that cocaine can amplify the immune response and cause neuroinflammation (Clark et al 2013) via dysfunction of the BBB (Dhillon et al 2008; Gandhi et al 2010) through alterations of tight junction proteins (Dhillon et al 2007), increased glial activation, and induction of neuroinflammatory pathways (Yao et al 2011; Kousik et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Zenón

Segarra

Gonzalez

et al. 2014

J Neuroimmune Pharmacol

View full text Add to dashboard Cite

Substance abuse is a risk factor for HIV infection and progression to AIDS. Recent evidence establishes that cocaine use promotes brain perivascular macrophage infiltration and microglia activation. The lysosomal protease cathepsin B is increased in monocytes from patients with HIV dementia and its secretion induces 10-15% of neurotoxicity. Here we asked if cocaine potentiates cathepsin B secretion from HIV-infected monocyte-derived macrophages (MDM) and its effect in neuronal apoptosis. Samples of plasma, CSF, and post-mortem brain tissue from HIV positive patients that used cocaine were tested for cathepsin B and its inhibitors to determine the in vivo relevance of these findings. MDM were inoculated with HIV-1ADA, exposed to cocaine, and the levels of secreted and bioactive cathepsin B and its inhibitors were measured at different time-points. Cathepsin B expression (p<0.001) and activity (p<0.05) increased in supernatants from HIV-infected cocaine treated MDM compared with HIV-infected cocaine negative controls. Increased levels of cystatin B expression was also found in supernatants from HIV-cocaine treated MDM (p<0.05). A significant increase in 30% of apoptotic neurons was obtained that decreased to 5% with the specific cathepsin B inhibitor (CA-074) or with cathepsin B antibody. Cathepsin B was significantly increased in the plasma and post-mortem brain tissue of HIV/cocaine users over non-drug users. Our results demonstrated that cocaine potentiates cathepsin B secretion in HIV-infected MDM and increase neuronal apoptosis. These findings provide new evidence that cocaine synergize with HIV-1 infection in increasing cathepsin B secretion and neurotoxicity.

show abstract

Adenosine Triphosphate Released from HIV-Infected Macrophages Regulates Glutamatergic Tone and Dendritic Spine Density on Neurons

Cited by 25 publications

References 52 publications

Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures

Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures

P2X-Selective Purinergic Antagonists Are Strong Inhibitors of HIV-1 Fusion during both Cell-to-Cell and Cell-Free Infection

Cocaine Potentiates Cathepsin B Secretion and Neuronal Apoptosis from HIV-Infected Macrophages

Contact Info

Product

Resources

About