A breakdown in astrocyte-neuronal axis of communication is emerging as a common feature in a number of neurodegenerative diseases, including HIV-Associated Neurocognitive Disorder (HAND). Even in the combined antiretroviral therapy era, HAND affects approximately 50% of HIV infected individuals and its prevalence is expected to increase as the HIV-infected population ages. This underscores the need to better define cellular and molecular mechanisms driving HIV-mediated neuropathogenesis to devise novel strategies to prevent and/or treat HAND. We determined that the Wnt/?-catenin pathway is a restriction factor for productive HIV replication in astrocytes. Wnt/?-catenin regulates cell structure, synaptic activity, cell proliferation, and survival. The central mediator of this pathwa (?-catenin) binds to TCF/LEF transcription factors and tethers on cognate genes to regulate their activity. We showed that ?-catenin restricts HIV by forming a complex with TCF-4 and SMAR-1 on the HIV LTR at site -143 from the +1 site to inhibit Pol II docking and consequently inhibits HIV transcription. These studies led to the first identification of functional TCF-4 bindig sites on the HIV promoter and established their prevalence in 500 HIV isolates. Interestingly, inflammatory mediators such as IFN? or HIV-1 Tat suppress ?-catenin activity while ?-catenin signaling inhibits the neuroinflammatory transcription factor CAAT/enhancer-binding proteins (C/EBP). We now provide evidence to suggest that disruption of Wnt/?-catenin in astrocytes negatively impact neurons. Specifically, we show that suppression of ?-catenin signaling in vitro and in vivo has a dramatic effect on the ability of astrocytes to scavenge for glutamate by inhibiting the expression of Excitatory Amino Acid Transporter 2 (EAAT-2/GLT-1 in rodents) and glutamine synthetase (GS). Excess glutamate is a common feature in neuroAIDS and other neurodegenerative diseases. Further, we show that higher plasma levels of Dickkopf-related protein 1 (DKK1, a soluble antagonist of Wnt signaling) are associated with worse global neurocognitive functioning among people living with HIV, suggesting that DKK1 may be a biomarker of HAND. These collective studies inform our central hypothesis which states that diminished ?-catenin signaling within astrocytes in response to an inflammatory mediator and/or HIV will perturb key functions of astrocytes and limit their neuroprotective properties. To test ths hypothesis, we will determine the functional consequences of diminished Wnt/?-catenin signaling in astrocytes on neuronal injury in vitro and in vivo (Aim 1), assess the ability of activators of Wnt/?-catenin signaling to reduce and/or ameliorate HIV associated neuroinflammatory processes by inhibiting C/EBP leading to reduction in proinflammatory cytokines/chemokines, astrocyte activation and leukocyte infiltration (Aim 2), and determine whether molecules related to Wnt/?-catenin signaling are clinical and neuropathological biomarkers of HAND using well-defied samples from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) and California NeuroAIDS Tissue Network (CNTN) studies. Together, these studies will advance our understanding of the interplay between a neuroprotective pathway (Wnt/?-catenin) and the astrocyte/neuronal axis of communication and in doing so will have a broader applicability to neurodegenerative diseases to provide a path for translational studies.

Public Health Relevance

One of the consequences of HIV infection is a spectrum of neurologic complications termed HIV-Associated Neurocognitive Disorder (HAND). Understanding mechanisms driving HAND will be highly beneficial for therapeutic intervention. This application will focus on revealing the role of a particular pathway known as Wnt/-catenin signaling in neuroAIDS. Based on extensive studies from our lab, we propose to study this pathway at the interface between astrocyte/neuron axis of communication in HAND

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060632-09
Application #
9298715
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
2008-09-29
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Wallace, Jennillee; Lutgen, Victoria; Avasarala, Sreedevi et al. (2018) Wnt7a induces a unique phenotype of monocyte-derived macrophages with lower phagocytic capacity and differential expression of pro- and anti-inflammatory cytokines. Immunology 153:203-213
Yu, Chunjiang; Narasipura, Srinivas D; Richards, Maureen H et al. (2017) HIV and drug abuse mediate astrocyte senescence in a ?-catenin-dependent manner leading to neuronal toxicity. Aging Cell 16:956-965
Yu, Chunjiang; Seaton, Melanie; Letendre, Scott et al. (2017) Plasma dickkopf-related protein 1, an antagonist of the Wnt pathway, is associated with HIV-associated neurocognitive impairment. AIDS 31:1379-1385
Lutgen, Victoria; Narasipura, Srinivas D; Sharma, Amit et al. (2016) ?-Catenin signaling positively regulates glutamate uptake and metabolism in astrocytes. J Neuroinflammation 13:242
Richards, Maureen H; Narasipura, Srinivas D; Seaton, Melanie S et al. (2016) Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling-Dependent Manner. J Immunol 196:317-27
Khodr, Christina E; Chen, Lihua; Dave, Sonya et al. (2016) Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons. Neurobiol Dis 94:85-94
Richards, Maureen H; Narasipura, Srinivas D; Kim, Stephanie et al. (2015) Dynamic interaction between astrocytes and infiltrating PBMCs in context of neuroAIDS. Glia 63:441-51
Aljawai, Yosra; Richards, Maureen H; Seaton, Melanie S et al. (2014) ?-Catenin/TCF-4 signaling regulates susceptibility of macrophages and resistance of monocytes to HIV-1 productive infection. Curr HIV Res 12:164-73
Narasipura, Srinivas D; Kim, Stephanie; Al-Harthi, Lena (2014) Epigenetic regulation of HIV-1 latency in astrocytes. J Virol 88:3031-8
Richards, Maureen H; Seaton, Melanie S; Wallace, Jennilee et al. (2014) Porcupine is not required for the production of the majority of Wnts from primary human astrocytes and CD8+ T cells. PLoS One 9:e92159

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