Despite effectiveness of HAART, prevalence of cognitive abnormalities has increased as HIV infected individuals live longer. Large numbers of HIV infected people exhibit some form of cognitive impairment, termed HAND. Monocytes/macrophages in the CNS are the best indicator of neurocognitive dysfunction, suggesting that monocyte transmigration across the blood brain barrier (BBS) is important in neuropathogenesis of AIDS. HIV infected opiate abusers have exacerbated CNS disease with increased inflammation and neuron injury that contribute to neurologic impairment.Opiate drug abuse augments NeuroAIDS. A new therapy for those addicted to opioids is buprenorphine, whose effects on immune cells and CNS vasculature have not been well characterized. How this drug impacts HIV-mediated neuropathological processes is unknown.Transmigration of monocytes across the BBB results in accumulation of monocytes/macrophages within the CNS, a hallmark of NeuroAIDS and its associated cognitive impairments. This inflammatory process is enhanced by opioid abuse. The chemokine CCL2 is highly elevated in the CNS of HIV infected people and mediates the enhanced transmigration of HIV-infected monocytes across the BBB. It is critical to evaluate the impact of buprenorphine as it may affect the transmigration of HIV infected monocytes and consequent neuroinflammation, as well as BBB function. Monocytes and brain microvascular endothelial cells (BMVEC) elaborate factors that enhance CNS damage. This proposal examines how buprenorphine alters HIV infected monocytes and the BBB to assess its impact on NeuroAIDS in the drug abusing population.
Specific aims :1. Examine membrane proteins on HIV infected monocytes that mediate their transmigration across the BBB to CCL2 and how they are altered by buprenorphine. Examine effects of buprenorphine on inflammatory mediators produced by monocytes and BMVEC. 2. Determine effects of buprenorphine on surface proteins and phosphorylation of signaling proteins in BMVEC that facilitate diapedesis of HIV infected monocytes to CCL2 and that maintain BBB integrity. 3. Determine changes in transmigration of HIV infected cells treated with buprenorphine in response to CCL2.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory Grants (P20)
Project #
5P20DA026149-02
Application #
8034374
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$119,794
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Nika, Heinz; Angeletti, Ruth Hogue; Hawke, David H (2016) Phosphopeptide Enrichment by Covalent Chromatography After Solid Phase Derivatization of Protein Digests on Reversed Phase Supports. Methods Mol Biol 1355:31-50
Arias, Franchesca; Arnsten, Julia H; Cunningham, Chinazo O et al. (2016) Neurocognitive, psychiatric, and substance use characteristics in opioid dependent adults. Addict Behav 60:137-43
Carvallo, Loreto; Lopez, Lillie; Che, Fa-Yun et al. (2015) Buprenorphine decreases the CCL2-mediated chemotactic response of monocytes. J Immunol 194:3246-58
Nika, Heinz; Angeletti, Ruth Hogue; Hawke, David H (2014) N-terminal protein characterization by mass spectrometry using combined microscale liquid and solid-phase derivatization. J Biomol Tech 25:77-86
Nika, Heinz; Hawke, David H; Angeletti, Ruth Hogue (2014) N-terminal protein characterization by mass spectrometry after cyanogen bromide cleavage using combined microscale liquid- and solid-phase derivatization. J Biomol Tech 25:19-30
Nika, Heinz; Hawke, David H; Angeletti, Ruth Hogue (2014) C-terminal protein characterization by mass spectrometry: isolation of C-terminal fragments from cyanogen bromide-cleaved protein. J Biomol Tech 25:1-18
Berezniuk, Iryna; Lyons, Peter J; Sironi, Juan J et al. (2013) Cytosolic carboxypeptidase 5 removes ?- and ?-linked glutamates from tubulin. J Biol Chem 288:30445-53
Fleitz, Antoine; Nieves, Edward; Madrid-Aliste, Carlos et al. (2013) Enhanced detection of multiply phosphorylated peptides and identification of their sites of modification. Anal Chem 85:8566-76
Nika, Heinz; Nieves, Edward; Hawke, David H et al. (2013) Phosphopeptide enrichment by covalent chromatography after derivatization of protein digests immobilized on reversed-phase supports. J Biomol Tech 24:154-77
Nika, Heinz; Nieves, Edward; Hawke, David H et al. (2013) Optimization of the ?-elimination/michael addition chemistry on reversed-phase supports for mass spectrometry analysis of O-linked protein modifications. J Biomol Tech 24:132-53

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