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)
Institute
National Institute of Mental Health (NIMH)
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
2001-12-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
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
Persidsky, Yuri; Hill, Jeremy; Zhang, Ming et al. (2016) Dysfunction of brain pericytes in chronic neuroinflammation. J Cereb Blood Flow Metab 36:794-807
Rom, Slava; Zuluaga-Ramirez, Viviana; Reichenbach, Nancy L et al. (2016) PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier. J Neuroinflammation 13:254
Gallek, Matthew J; Skoch, Jesse; Ansay, Tracy et al. (2016) Cortical gene expression: prognostic value for seizure outcome following temporal lobectomy and amygdalohippocampectomy. Neurogenetics 17:211-218
Zuluaga-Ramirez, Viviana; Rom, Slava; Persidsky, Yuri (2015) Craniula: A cranial window technique for prolonged imaging of brain surface vasculature with simultaneous adjacent intracerebral injection. Fluids Barriers CNS 12:24
Watters, Andrea K; Rom, Slava; Hill, Jeremy D et al. (2015) Identification and dynamic regulation of tight junction protein expression in human neural stem cells. Stem Cells Dev 24:1377-89
Rom, Slava; Dykstra, Holly; Zuluaga-Ramirez, Viviana et al. (2015) miR-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions. J Cereb Blood Flow Metab 35:1957-65
Rom, Slava; Zuluaga-Ramirez, Viviana; Dykstra, Holly et al. (2015) Poly(ADP-ribose) polymerase-1 inhibition in brain endothelium protects the blood-brain barrier under physiologic and neuroinflammatory conditions. J Cereb Blood Flow Metab 35:28-36
Persidsky, Yuri; Fan, Shongshan; Dykstra, Holly et al. (2015) Activation of Cannabinoid Type Two Receptors (CB2) Diminish Inflammatory Responses in Macrophages and Brain Endothelium. J Neuroimmune Pharmacol 10:302-8
Persidsky, Yuri (2015) Insights into end-organ injury in HIV infection: dynamics of monocyte trafficking to the brain in SIV encephalitis. Am J Pathol 185:1548-51
Rom, Slava; Reichenbach, Nancy L; Dykstra, Holly et al. (2015) The dual action of poly(ADP-ribose) polymerase -1 (PARP-1) inhibition in HIV-1 infection: HIV-1 LTR inhibition and diminution in Rho GTPase activity. Front Microbiol 6:878

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