As of 2007, an estimated 33 million persons worldwide were living with human immunodeficiency virus (HIV) infection (Word Health Organization and UN estimations). Early after primary infection, HIV enters the CNS and causes cognitive and motor impairment in 30-60 % of infected individuals, even in the antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications due to HIV CNS infection has increased. The cellular basis and mechanisms, by which HIV-1 causes neuropathogenesis, or NeuroAIDS, are still not well understood. Astrocytes are key cells in the CNS that regulate BBB integrity, CNS inflammation, immune responses and neuronal survival. HIV only infects a small percentage of these cells and low viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and hemichannels, can amplify inflammation and CNS damage. Our proposal hypothesizes that Cx43 containing GJ and hemichannels amplify intracellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, astrocyte proliferation, BBB disruption and secretion of DKK1 leading to the enhanced CNS dysfunction often observed in the HIV infected population even in the current antiretroviral era, where viral replication is minimal. To address this hypothesis we will expand upon our extensive Preliminary Studies demonstrating the participation of these channels in neuronal, astrocyte and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes as well as in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels during the viral life cycle in astrocytes. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS.

Public Health Relevance

As individuals with HIV are living longer due to the success of antiretroviral therapies; the prevalence of cognitive and motor deficits in this infected population is increasing. Astrocytes play a key role in maintaining CNS functions. However; their role in the pathogenesis of NeuroAIDS has not been well characterized; mainly due to the lack of specific molecular tools to examine HIV infection of astrocytes. We and others developed techniques to examine HIV infection of astrocytes in vivo and in vitro and their consequences in brain physiology using gap junction and hemichannels. Our studies already demonstrated that gap junction and hemichannels of Connexin43 (Cx43) are critical to spread damage to neighboring cells despite the few numbers of HIV infected cells and low viral replication. We propose to expand these studies to characterize bystander dysregulation of uninfected astrocytes; neurons and brain endothelial cells. In addition; we will study the molecular mechanism by which gap junction and hemichannels transmit and amplify toxic signals to neighboring cells by examining their activation and regulation. Lastly; we will expand our preliminary data obtained in vivo by using a novel animal model of bystander toxicity mediated by microinjection of few human HIV infected human astrocytes into the brain of animals with astrocytes genetically deleted for Cx43 and to evaluate apoptosis; astrocyte proliferation and BBB disruption in neighboring cells around the microinjected HIV infected astrocytes. The results of these studies may provide information for the development of therapies to treat the neurologic dysfunctions in HIV infected individuals

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH096625-03
Application #
8793824
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2012-05-07
Project End
2017-03-31
Budget Start
2013-07-01
Budget End
2014-03-31
Support Year
Fiscal Year
2013
Total Cost
$223,570
Indirect Cost
$82,960
Name
Rutgers University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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