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
Orellana, Juan Andres; Saez, Juan Carlos; Bennett, Michael Vander Lann et al. (2014) HIV increases the release of dickkopf-1 protein from human astrocytes by a Cx43 hemichannel-dependent mechanism. J Neurochem 128:752-63
Rella, Courtney E; Ruel, Nancy; Eugenin, Eliseo A (2014) Development of imaging techniques to study the pathogenesis of biosafety level 2/3 infectious agents. Pathog Dis 72:167-73
Subbian, Selvakumar; Eugenin, Eliseo; Kaplan, Gilla (2014) Detection of Mycobacterium tuberculosis in latently infected lungs by immunohistochemistry and confocal microscopy. J Med Microbiol 63:1432-5
Rao, Vasudev R; Neogi, Ujjwal; Eugenin, Eliseo et al. (2014) The gp120 protein is a second determinant of decreased neurovirulence of Indian HIV-1C isolates compared to southern African HIV-1C isolates. PLoS One 9:e107074
Daep, Carlo Amorin; Muñoz-Jordán, Jorge L; Eugenin, Eliseo Alberto (2014) Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus. J Neurovirol 20:539-60
Eugenin, Eliseo A (2014) Role of connexin/pannexin containing channels in infectious diseases. FEBS Lett 588:1389-95
Chung, S; Yao, J; Suyama, K et al. (2013) N-cadherin regulates mammary tumor cell migration through Akt3 suppression. Oncogene 32:422-30
Rao, Vasudev R; Neogi, Ujjwal; Talboom, Joshua S et al. (2013) Clade C HIV-1 isolates circulating in Southern Africa exhibit a greater frequency of dicysteine motif-containing Tat variants than those in Southeast Asia and cause increased neurovirulence. Retrovirology 10:61
D'Aversa, T G; Eugenin, E A; Lopez, L et al. (2013) Myelin basic protein induces inflammatory mediators from primary human endothelial cells and blood-brain barrier disruption: implications for the pathogenesis of multiple sclerosis. Neuropathol Appl Neurobiol 39:270-83
Williams, Dionna W; Calderon, Tina M; Lopez, Lillie et al. (2013) Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis. PLoS One 8:e69270

Showing the most recent 10 out of 14 publications