As of 2010, an estimated 34 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 minimal to undetectable viral production is detected. Nevertheless, our data demonstrate for first time that HIV infected astrocytes, through gap junction channels and perhaps hemichannels, can amplify inflammation and CNS damage. We hypothesize that Cx43 containing gap junctions (GJ) and hemichannels (uHC) amplify intercellular signals generated in few HIV infected astrocytes to surrounding uninfected cells resulting in cellular toxicity, BBB disruption and secretion of DKK1 leading to the 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 astrocyte, neuronal and blood brain barrier (BBB) dysfunction, as well in amplification of cell activation and inflammation in HIV infected astrocytes and in uninfected cells. These data will characterize novel pathways of HIV toxicity within the brain and will identify the role of these channels in CNS dysfunction. The results obtained from this proposal should indicate potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

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 populatio 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. The development of novel techniques to examine HIV infection of astrocytes in vivo and in vitro and their consequences in brain enable us to demonstrate that gap junction (GJ) and hemichannels (uHC) in astrocytes are important in the pathogenesis of NeuroAIDS. Our studies already showed that GJ and uHC of Connexin43 (Cx43) are critical to spread damage to neighboring cells despite the few numbers of HIV infected cells and minimal 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 GJ and uHC transmit and amplify toxic signals to neighboring cells by examining their activation and regulation. Lastly, we will expand upon 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. We will evaluate using these animals, apoptosis 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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Medicine & Dentistry of NJ
Public Health & Prev Medicine
Schools of Medicine
United States
Zip Code
Prevedel, Lisa; Ruel, Nancy; Castellano, Paul et al. (2018) Identification, Localization, and Quantification of HIV Reservoirs Using Microscopy. Curr Protoc Cell Biol :e64
Zimmerman, Matthew; Blanc, Landry; Chen, Pei-Yu et al. (2018) Spatial Quantification of Drugs in Pulmonary Tuberculosis Lesions by Laser Capture Microdissection Liquid Chromatography Mass Spectrometry (LCM-LC/MS). J Vis Exp :
Valdebenito, Silvana; Lou, Emil; Baldoni, John et al. (2018) The Novel Roles of Connexin Channels and Tunneling Nanotubes in Cancer Pathogenesis. Int J Mol Sci 19:
Megra, Bezawit W; Eugenin, Eliseo A; Berman, Joan W (2018) Inflammatory mediators reduce surface PrPc on human BMVEC resulting in decreased barrier integrity. Lab Invest 98:1347-1359
Valdebenito, Silvana; Barreto, Andrea; Eugenin, Eliseo A (2018) The role of connexin and pannexin containing channels in the innate and acquired immune response. Biochim Biophys Acta Biomembr 1860:154-165
Malik, Shaily; Theis, Martin; Eugenin, Eliseo A (2017) Connexin43 Containing Gap Junction Channels Facilitate HIV Bystander Toxicity: Implications in NeuroHIV. Front Mol Neurosci 10:404
Calderon, Tina M; Williams, Dionna W; Lopez, Lillie et al. (2017) Dopamine Increases CD14+CD16+ Monocyte Transmigration across the Blood Brain Barrier: Implications for Substance Abuse and HIV Neuropathogenesis. J Neuroimmune Pharmacol 12:353-370
Prevedel, Lisa; Morocho, Camilla; Bennett, Michael V L et al. (2017) HIV-Associated Cardiovascular Disease: Role of Connexin 43. Am J Pathol 187:1960-1970
Megra, Bezawit W; Eugenin, Eliseo A; Berman, Joan W (2017) The Role of Shed PrPc in the Neuropathogenesis of HIV Infection. J Immunol 199:224-232
Mishra, Bibhuti B; Lovewell, Rustin R; Olive, Andrew J et al. (2017) Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis. Nat Microbiol 2:17072

Showing the most recent 10 out of 64 publications