One in three HIV-infected individuals develops some form of HIV-associated neurocognitive disorder (HAND). Consumption of drugs of abuse such as methamphetamine (METH) aggravates the symptoms of HAND, but the cellular and molecular mechanisms by which these drugs impact HIV disease progression in the central nervous system (CNS) remain ill-defined. In this study will test the hypothesis that HAND arises from the intermittent reactivation of latently infected microglial cells leading to the expression f the neurotoxic viral proteins, Tat and gp120. Specifically, we will identify the specific contributon of specific molecular networks of glial cells that are involved in the control of HIV latency and te acquisition of an anti-inflammatory M2 phenotype. Our recent unbiased human shRNA library screen for factors that are required to maintain HIV latency in CHME-5/HIV cells showed that HIV silencing in microglila cells can be induced by the ligand- activated nuclear receptors (LA-NR) PPAR, RAR and RXR. Chemical screens of PPAR, RAR and RXR agonists and antagonists confirmed that these receptors have a critical regulatory role in controlling HIV latency in microglial cells and that receptor agonists are potent blockers of HIV reactivation. In this study we will study the molecular basis for LA-NR control of HIV transcription in microglial cells and how this regulatory pathway is modified by METH. Using novel co-culture systems between latently infected microglial cells and neurons we will study the impact METH on the induction of latent HIV proviruses and their subsequent neurotoxicity. We will also use this system to evaluate the neuroprotective effects of PPAR, RAR and RXR agonists, consistent with the recent demonstration that the RXR agonist bexarotene or the PPAR agonist pioglitazone are neuroprotective in mouse models of Alzheimer's disease. Finally we will evaluate the role of the ligand nuclear receptor pathway on HIV induced neurodegeneration using a novel double transgenic mouse model, JR-CSF/hu-CycT1 mice, that permits HIV replication in mouse cells and allows study of how HIV infection induces brain dysfunction. We also plan to develop a novel model for HIV-induced neurodegeneration using latently infected mouse monocytes to repopulate the brains of CD11b-HSVTK transgenic mice where microglial cells have been depleted. The multidisciplinary experiments described in this application represent a comprehensive evaluation of the molecular basis for HIV latency in microglial cells in the brain, the impact of METH on HIV latency and neurodegeneration, and extensive evaluations of the potential of nuclear receptor agonists as neuroprotective agents. We believe that the systematic studies we have proposed here will set the stage for improved clinical management of HIV-associated dementia (HAD) and minor cognitive motor disorder (MCMD) in our patients who abuse drugs.

Public Health Relevance

Consumption of drugs of abuse such as methamphetamine (METH) aggravates the symptoms of HIV- associated neurocognitive disorder (HAND) by inducing inflammatory reactions in the brain that stimulate HIV replication in microglial cells, th resident immune system cells in the brain. We have recently discovered that a novel class of anti-inflammatory drugs called ligand-activated nuclear receptor agonists are neuroprotective against HIV ex vivo. We will expand these studies using novel transgenic mouse models for HAND to identify novel therapies for HIV-associated dementia (HAND) in our patients who abuse drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA036171-02
Application #
8683139
Study Section
Special Emphasis Panel (ZDA1-GXM-A (08))
Program Officer
Satterlee, John S
Project Start
2013-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$718,338
Indirect Cost
$204,035
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Tilton, Carisa A; Tabler, Caroline O; Lucera, Mark B et al. (2014) A combination HIV reporter virus system for measuring post-entry event efficiency and viral outcome in primary CD4+ T cell subsets. J Virol Methods 195:164-9
Mbonye, Uri; Karn, Jonathan (2014) Transcriptional control of HIV latency: cellular signaling pathways, epigenetics, happenstance and the hope for a cure. Virology 454-455:328-39
Katsumoto, Atsuko; Lu, Haiyan; Miranda, Aline S et al. (2014) Ontogeny and functions of central nervous system macrophages. J Immunol 193:2615-21