Intravenous drug use and HIV infections are two linked global health crises since needle sharing is a well recognized mode of HTV transmission. While HIV infection is the leading cause of death among Americans 25- 44 years old, injection drug use now accounts for about one-third of all new US AIDS cases reported each year. Cocaine, often abused by HIV-infected patients, has been suggested to worsen the HIV-associated dementia (HAD) via unknown mechanisms. The brain is a target organ for both, the recreational drugs and HIV-1. HAD is an important complication of viral infection and a cause of significant morbidity, and mortality. The underlying feature of HAD revolves around two processes: a) productive replication of the virus in macrophages in the brain, leading to encephalitis, and b) neuronal degeneration resulting from the action of secreted byproducts released from infected macrophages, leading to dementia. Cocaine IVDUs are known to have higher rates of HIV-encephalitis, microglial proliferation and clinical HIV dementia. The use of cocaine therefore exacerbates factors that promote HIV replication in the brain. Our preliminary studies demonstrated that cocaine enhanced production of both, the virus and of the virus-promoting cytokine, IL-10 in monocyte-derived macrophages (MDMs). Cocaine also synergized with viral glycoprotein, gp120, to induce the expression of the neurotoxin, CXCL10 in human neuronal cultures. Based on these findings, we hypothesize that cocaine accelerates the progression of HIV-E by two mechanisms: 1) Cocaine-mediated induction of IL-10 enhances virus-replication in the brain, and 2) synergistic induction of CXCL10 by cocaine &gp120 accelerates neuronal dysfunction/death. In this application we will test the hypotheses in 3 specific aims: 1) Examine the role of IL-10 in cocaine-mediated up-regulation of SHIV/HIV-1 replication in macaque/human MDM cultures, 2) To determine the mechanism(s) of cocaine &virus protein induced-CXCL10 on neuronal dysfunction/death in vitro. 3) In vivo abrogation of cocaine and gp120-mediated neuronal apoptosis using antisense CXCL10 DNA therapy in murine models of HTV-dementia. Relevance: This proposal aims to: a) Explore the role of cocaine in accelerating the development of HFV Dementia and b) Develop therapeutic intervention strategies for the treatment of HAD in cocaine-abusers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA020392-06
Application #
7845008
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Lawrence, Diane M
Project Start
2006-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
6
Fiscal Year
2010
Total Cost
$279,793
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
Yang, Lu; Yao, Honghong; Chen, Xufeng et al. (2016) Role of Sigma Receptor in Cocaine-Mediated Induction of Glial Fibrillary Acidic Protein: Implications for HAND. Mol Neurobiol 53:1329-42
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
Marcario, Joanne K; Pendyala, Gurudutt; Riazi, Mariam et al. (2016) Effects of Morphine on Behavioral Task Performance in SIV-Infected Rhesus Macaques. J Neuroimmune Pharmacol 11:348-57
Ma, Rong; Yang, Lu; Niu, Fang et al. (2016) HIV Tat-Mediated Induction of Human Brain Microvascular Endothelial Cell Apoptosis Involves Endoplasmic Reticulum Stress and Mitochondrial Dysfunction. Mol Neurobiol 53:132-142
Pendyala, Gurudutt; Periyasamy, Palsamy; Callen, Shannon et al. (2015) Chronic SIV and morphine treatment increases heat shock protein 5 expression at the synapse. J Neurovirol 21:592-8
Yao, Honghong; Bethel-Brown, Crystal; Niu, Fang et al. (2014) Yin and Yang of PDGF-mediated signaling pathway in the context of HIV infection and drug abuse. J Neuroimmune Pharmacol 9:161-7
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
Yao, Honghong; Ma, Rong; Yang, Lu et al. (2014) MiR-9 promotes microglial activation by targeting MCPIP1. Nat Commun 5:4386
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

Showing the most recent 10 out of 44 publications