HIV-1 infection of the central nervous system (CNS) occurs in a majority of AIDS patients and causes a variety of neurologic dysfunction and neuropathologies generally termed neuroAIDS. Microglia/macrophages, and astrocytes to a less extent are the main target cells for HIV-1 infection in the CNS, whereas neurons are rarely infected by HIV-1 but mostly affected in HIV/neuroAIDS. Therefore, several indirect mechanisms have been proposed for HIV/neuroAIDS pathogenesis. Among them is HIV-1 Tat protein. We have shown that Tat expression in the absence of HIV-1 infection is sufficient to cause neurobehavioral abnormalities and pathologies similar to most of those noted in HIV/neuroAIDS. Moreover, we have shown that Tat activates glial fibrillary acidic protein (GFAP) expression in astrocytes and results in astrocyte dysfunction and subsequent neuron death. Furthermore, our preliminary studies have found that Tat-activated GFAP expression involves a network of transcription factors and is associated with GFAP aggregates and endoplasmic reticulum (ER) stress in astrocytes and impaired neuron survival. Importantly, we have also obtained preliminary evidence to link the cerebrospinal fluid (CSF) levels to HIV/neuroAIDS pathogenesis. As a logical extension of our studies, we propose to further dissect the GFAP function in Tat neurotoxicity and HIV/neuroAIDS pathogenesis. Besides, we will determine the feasibility of using the CSF GFAP level as a novel HIV/neuroAIDS biomarker. Thus, the underlying hypothesis for the current proposal is that Tat adversely affects astrocyte function and neuronal survival through GFAP activation/aggregation and ER stress. In other words, GFAP is not only a mediator but also an indicator of Tat neurotoxicity and HIV/neuroAIDS pathogenesis. To test this hypothesis, we propose to address the following interrelated specific aims: (1) To characterize the relationship between GFAP expression and ER stress in astrocytes;(2) To determine effects of Tat-activated GFAP expression/aggregation and ER stress on astrocytes;(3) To define the molecular mechanisms of GFAP-/ER stress-mediated neurotoxicity;and (4) To investigate the potential of using GFAP as a novel HIV/neuroAIDS biomarker. We will use a combined molecular, cellular, biochemical, and genetic approach, including use of primary mouse cortical astrocyte cultures and neuron cultures, Tat transgenic mice, GFAP-null/Tat transgenic mice, primary human fetal brain cultures, embedded brain tissues and CSF samples of a large HIV-1 cohort in our studies. The answers sought have fundamental significance for understanding of this critical and pervasive protein GFAP, and its role in HIV/neuroAIDS pathogenesis. In addition, these answers shall also aid in identification of HIV/neuroAIDS biomarkers and development of anti-HIV/neuroAIDS therapeutic strategies.

Public Health Relevance

HIV-1 infection often causes a number of brain diseases and affects the ability of people to care for themselves and thus the quality of their daily life. The social and economic impact cannot be overemphasized. The current study seeks to have a better understanding of the host factors that are important for the disease progression and then use the knowledge acquired to develop new markers to monitor the disease progression and treatment response and develop new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH092673-05
Application #
8442887
Study Section
Special Emphasis Panel (ZRG1-AARR-K (02))
Program Officer
Joseph, Jeymohan
Project Start
2010-08-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$460,432
Indirect Cost
$141,195
Name
University of North Texas
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Rahimian, Pejman; He, Johnny J (2016) HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression. J Neuroinflammation 13:247
Rahimian, Pejman; He, Johnny J (2016) HIV/neuroAIDS biomarkers. Prog Neurobiol :
Fan, Yan; He, Johnny J (2016) HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity. J Biol Chem 291:22830-22840
Fan, Yan; Gao, Xiang; Chen, Jinhui et al. (2016) HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway. J Neurosci 36:11362-11373
Fan, Yan; He, Johnny J (2016) HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation. J Biol Chem 291:22819-22829
Fan, Yan; Timani, Khalid Amine; He, Johnny J (2015) STAT3 and its phosphorylation are involved in HIV-1 Tat-induced transactivation of glial fibrillary acidic protein. Curr HIV Res 13:55-63
Luo, Xiaoyu; He, Johnny J (2015) Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes. J Neurovirol 21:66-80
Luo, Xiaoyu; Fan, Yan; Park, In-Woo et al. (2015) Exosomes are unlikely involved in intercellular Nef transfer. PLoS One 10:e0124436
Zhao, Weina; Liu, Ying; Timani, Khalid Amine et al. (2014) Tip110 protein binds to unphosphorylated RNA polymerase II and promotes its phosphorylation and HIV-1 long terminal repeat transcription. J Biol Chem 289:190-202
Paris, Jason J; Carey, Amanda N; Shay, Christopher F et al. (2014) Effects of conditional central expression of HIV-1 tat protein to potentiate cocaine-mediated psychostimulation and reward among male mice. Neuropsychopharmacology 39:380-8

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