HIV-associated dementia (HAD) is an important complication of viral infection and a cause of significant morbidity and mortality. Although the primary cell types infected by HIV-1 in the brain are macrophages/microglia, and to a lesser extent, astrocytes but NOT neurons, the low numbers of infected cells in the brain do not correlate with the extent of neuropathogenesis observed in HIV encephalitis (HIV-E). Instead, activation of glia through direct infection or their interactions with infected cells, their products, or viral particles, contribute to the severe neuropathological abnormalities associated with HAD. It is becoming increasingly evident that the interplay of factors (cytokines, chemokines and/or viral proteins) released from activated astroglial cells play a crucial role in orchestrating the amplification of toxic inflammatory cascades that ultimately lead to progressive loss of neuronal function. While the previous period of funding was focused on identifying soluble mediators that were involved in the pathogenesis of X4 SHIV/Rhesus macaque model of NeuroAIDS, the renewal will focus on viral &cellular interactive loops in the generation of the neurotoxin, CXCL10, in the context of R5 viruses, with relevance to human CNS disease. Two aspects will be considered for these studies: a) synergistic effect of HIV-1/viral proteins in the induction of IFN-3 inducible neurotoxin, CXCL10 and b) PDGF-mediated neuroprotection against combined toxicity of viral proteins/cytokines &CXCL10. Such a combinatorial approach is consistent with the long-term translational goal of developing novel experimental therapeutics for HAD that will be aimed at mitigating CXCL10 toxicity and concomitant neuronal degeneration in the CNS. Proposed hypotheses will be tested in three specific aims: 1) To examine the synergistic effects of HIV-1 proteins, and pro-inflammatory cytokines on CXCL10 gene expression by astrocytes;2) To investigate the role of PDGF in protection against viral protein/cytokine/CXCL10-mediated neuronal apoptosis &3) In vivo delivery of antisense CXCL10 &PDGF DNA as therapy for abrogating HIV-neurotoxicity in murine models of HIV-1 CNS disease.

Public Health Relevance

This proposal aims to: a) Explore the interplay of vial and/or host factors in mediating astrocyte activation &neuronal dysfunction and, b) Develop therapeutic intervention strategies aimed at reducing HIV neurotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068212-08
Application #
7792250
Study Section
Special Emphasis Panel (ZRG1-AARR-D (05))
Program Officer
Joseph, Jeymohan
Project Start
2003-04-01
Project End
2013-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
8
Fiscal Year
2010
Total Cost
$350,963
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Hu, Guoku; Liao, Ke; Yang, Lu et al. (2017) Tat-Mediated Induction of miRs-34a & -138 Promotes Astrocytic Activation via Downregulation of SIRT1: Implications for Aging in HAND. J Neuroimmune Pharmacol 12:420-432
Yang, Lu; Chen, Xufeng; Hu, Guoku et al. (2016) Mechanisms of Platelet-Derived Growth Factor-BB in Restoring HIV Tat-Cocaine-Mediated Impairment of Neuronal Differentiation. Mol Neurobiol 53:6377-6387
Buch, Shilpa (2014) Growth factor signaling: implications for disease & therapeutics. J Neuroimmune Pharmacol 9:65-8
Chao, Jie; Yang, Lu; Yao, Honghong et al. (2014) Platelet-derived growth factor-BB restores HIV Tat -mediated impairment of neurogenesis: role of GSK-3?/?-catenin. J Neuroimmune Pharmacol 9:259-68
Duan, Ming; Yao, Honghong; Cai, Yu et al. (2014) HIV-1 Tat disrupts CX3CL1-CX3CR1 axis in microglia via the NF-?BYY1 pathway. Curr HIV Res 12:189-200
Yao, Honghong; Ma, Rong; Yang, Lu et al. (2014) MiR-9 promotes microglial activation by targeting MCPIP1. Nat Commun 5:4386
Yao, Honghong; Duan, Ming; Yang, Lu et al. (2013) Nonmuscle myosin light-chain kinase mediates microglial migration induced by HIV Tat: involvement of ?1 integrins. FASEB J 27:1532-48
Duan, Ming; Yao, Honghong; Hu, Guoku et al. (2013) HIV Tat induces expression of ICAM-1 in HUVECs: implications for miR-221/-222 in HIV-associated cardiomyopathy. PLoS One 8:e60170
Yang, L; Chao, J; Kook, Y H et al. (2013) Involvement of miR-9/MCPIP1 axis in PDGF-BB-mediated neurogenesis in neuronal progenitor cells. Cell Death Dis 4:e960
Peng, Fuwang; Yao, Honghong; Akturk, Halis Kaan et al. (2012) Platelet-derived growth factor CC-mediated neuroprotection against HIV Tat involves TRPC-mediated inactivation of GSK 3beta. PLoS One 7:e47572

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