Prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the introduction of combined antiretroviral therapy. HAND is associated with elevation of pro-inflammatory factors in blood and subsets of activated infected monocytes, both shown to cause blood brain barrier (BBB) impairment that contributes to HAND. Therapeutic strategies that disrupt monocyte migration can slow progression of HIV infection and BBB injury, thereby ameliorating HAND. During the previous period of funding, we focused on studies of (1) molecular mechanisms of BBB injury and (2) anti-inflammatory and barrier protective properties of glycogen synthase kinase (GSK) 3? inhibition in neuroinflammation driven by HIV infection. We uncovered molecular mechanisms of BBB dysfunction [tight junction (TJ) phosphorylation, CD40/CD40 ligand interactions at BBB and signaling events behind the direct effects of HIV on brain endothelium]. We demonstrated barrier tightening following GSK3? suppression in brain endothelium due to TJ stabilization. We uncovered potent anti-inflammatory effects of GSK3? inhibition in brain endothelium (suppression of monocyte migration, diminution of inflammatory factor production, and BBB protection) in vitro and in vivo. GSK? inhibition in monocytes attenuated their adhesion/migration across the BBB, down regulated active integrin expression via suppression of the small GTPase, Rac1, and protected the BBB. Yet, BBB shielding properties or inhibition of monocyte migration/adhesion were not fully attained in vitro or in vivo, suggesting that additional pathways complimentary to GSK3? are necessary for the restitution of BBB function. In search of such molecules, we turned our attention to poly(ADP-ribose) polymerase-1 (PARP-1) and its inhibitors, recently recognized as anti-inflammatory/immune modulating agents with significant neuroprotective properties. Based upon preliminary data, we propose that PARP inhibition will attenuate BBB injury caused by HIV-1 via effects on monocytes, brain endothelium, activated microglia and HIV-1 infected macrophages. Indeed, preliminary data indicate that PARP suppression in primary human brain microvascular endothelial cells (BMVEC) improved BBB integrity and augmented expression of TJ proteins. PARP inhibitors prevented barrier disruption caused by inflammatory factors, diminished monocyte adhesion/migration across a BBB model, down regulated adhesion molecules/pro-inflammatory molecules and decreased activity of RhoA/Rac1. In monocytes, PARP inhibitors down regulated the active ?-integrin that paralleled RhoA/Rac1 suppression. PARP inhibitors decreased expression of pro-inflammatory molecules and diminished HIV replication in human macrophages. Although the modulatory effects of PARP inhibitors on immune cells have been studied to some extent, nothing is known about their effects in the setting of HIV CNS infection. PARP inhibitors have now reached the stage of clinical testing for cancer treatment, assuring quick translation to therapy of immune/inflammatory disorders.

Public Health Relevance

Prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite the introduction of combined antiretroviral therapy, and adjunctive treatment modalities are necessary. We propose novel approach to ameliorate HAND via poly (ADP-ribose) polymerase-1 (PARP-1) inhibition. We hypothesized PARP-1 suppression will diminished injury of blood brain barrier caused by HIV-1 due its effects in infected leukocytes (monocytes and macrophages) and brain endothelium. Although the modulatory effects of PARP inhibitors on immune cells have been studied to some extent, nothing is known about their effects in the setting of HIV brain infection. PARP inhibitors have now reached the stage of clinical testing for cancer treatment, assuring quick translation to therapy of immune/inflammatory disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH065151-13
Application #
8690971
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Colosi, Deborah
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Haskó, János; Fazakas, Csilla; Molnár, Judit et al. (2014) CB2 receptor activation inhibits melanoma cell transmigration through the blood-brain barrier. Int J Mol Sci 15:8063-74
Hill, Jeremy; Rom, Slava; Ramirez, Servio H et al. (2014) Emerging roles of pericytes in the regulation of the neurovascular unit in health and disease. J Neuroimmune Pharmacol 9:591-605
Rom, Slava; Zuluaga-Ramirez, Viviana; Dykstra, Holly et al. (2013) Selective activation of cannabinoid receptor 2 in leukocytes suppresses their engagement of the brain endothelium and protects the blood-brain barrier. Am J Pathol 183:1548-58
Ramirez, Servio H; Fan, Shongshan; Dykstra, Holly et al. (2013) Inhibition of glycogen synthase kinase 3ýý promotes tight junction stability in brain endothelial cells by half-life extension of occludin and claudin-5. PLoS One 8:e55972
Rom, Slava; Persidsky, Yuri (2013) Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol 8:608-20
Ramirez, Servio H; Reichenbach, Nancy L; Fan, Shongshan et al. (2013) Attenuation of HIV-1 replication in macrophages by cannabinoid receptor 2 agonists. J Leukoc Biol 93:801-10
Ramirez, Servio H; Hasko, Janos; Skuba, Andrew et al. (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004-16
Witte, Marlys H (2011) Translational/personalized medicine, pharmaco/surgico/radiogenomics, lymphatic spread of cancer, and medical ignoromes. J Surg Oncol 103:501-7
Ashraf, Tamima; Ronaldson, Patrick T; Persidsky, Yuri et al. (2011) Regulation of P-glycoprotein by human immunodeficiency virus-1 in primary cultures of human fetal astrocytes. J Neurosci Res 89:1773-82
Persidsky, Yuri; Ho, Wenzhe; Ramirez, Servio H et al. (2011) HIV-1 infection and alcohol abuse: neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions. Brain Behav Immun 25 Suppl 1:S61-70

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