Astrocyte Elevated Gene-1 Is a Novel Modulator of HIV-1-associated Neuroinflammation via Regulation of Nuclear Factor-κB Signaling and Excitatory Amino Acid Transporter-2 Repression

Vartak-Sharma, Neha; Gelman, Benjamin B.; Joshi, Chaitanya R.; Borgamann, Kathleen; Ghorpade, Anuja

doi:10.1074/jbc.m114.567644

Cited by 49 publications

(53 citation statements)

References 67 publications

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“…Glutamine is a trophic amino acid produced largely in astrocytes by a glutamine synthase mediated conversion of glutamate to glutamine. HIV infection, encephalitis, HIV-gp120, Tat, tumour necrosis factor α and interleukin-1β impair glutamate uptake [59,60], and gp120 is known to reduce glutamine levels and survival of cultured astrocytes [61]. Free radical scavenging with N -acetylcysteine protects astrocytes from gp120 and increases glutamine concentrations [61].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients

Dickens

Anthony

Deutsch

et al. 2015

Aids

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Objectives To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients. Design Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV+ patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening. Methods The metabolic composition of CSF was analysed using 1HNMR spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features. Results Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, β-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%. Conclusion These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients

Dickens

Anthony

Deutsch

et al. 2015

Aids

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“…AEG-1 was often induced as a late onset gene 3–7 days post-HIV-1 exposure and/or TNF-α treatment (Su et al , 2002). In our studies in cultured human astrocytes, HIV-1 and TNF-α induced AEG-1 expression earlier, within 8 h for RNA and 24 h for protein (Vartak-Sharma et al , 2014). …”

Section: Aeg-1: Historical Perspectivesmentioning

confidence: 64%

“…HIVE is a pathological manifestation of the clinical stage IV of HIV-1 CNS infection. Our immunohistochemical and immunoblotting analysis of 12 HIV-1 without encephalitis and 11 HIVE brain tissue specimens revealed significant AEG-1 upregulation with HIV-1 CNS disease progression, suggesting its involvement in HIV-1-associated neurological complications (Vartak-Sharma et al , 2014). …”

Section: Aeg-1: Historical Perspectivesmentioning

confidence: 82%

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Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

Vartak-Sharma

Nooka

Ghorpade

2017

Progress in Neurobiology

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Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocytes uncovered a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1). Our previous studies revealed that AEG-1 regulates reactive astrocytes proliferation, migration and inflammation, all hallmarks of aging and CNS injury. Moreover, the involvement of AEG-1 in neurodegenerative disorders, such as Huntington’s disease and migraine, and its induction in the aged brain suggest a plausible role in regulating overall CNS homeostasis and aging. Therefore, it is important to investigate AEG-1 specifically in aging-associated cognitive decline. In this study, we decipher the common mechanistic links in cancer, aging and HIV-1-associated neurocognitive disorders that likely contribute to AEG-1-based regulation of astrocyte responses and function. Despite AEG-1 incorporation into HIV-1 virions and its induction by HIV-1, tumor necrosis factor-α and interleukin-1β, the specific role(s) of AEG-1 in astrocyte-driven HIV-1 neuropathogenesis are incompletely defined. We propose that AEG-1 plays a central role in a multitude of cellular stress responses involving mitochondria, endoplasmic reticulum and the nucleolus. It is thus important to further investigate AEG-1-based cellular and molecular regulation in order to successfully develop better therapeutic approaches that target AEG-1 to combat cancer, HIV-1 and aging.

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“…Additionally, altered BBB permeability can increase neuroinflammation and contribute to disease. These mechanisms precede or succeed neurodegeneration and overlap in diseases such as Alzheimer’s disease (AD) [A1(Uylings and De Brabander, 2002), A2 (Wake et al, 2013), A3 (Wyss-Coray and Rogers, 2012), A4 (Alberdi et al, 2013), A5 (Fuller et al, 2009), A6 (Allen and Barres, 2009)], Amyotrophic lateral sclerosis (ALS) [B1 (Evans et al, 2013), B2 (Manfredi and Xu, 2005), B3 (Grosskreutz et al, 2010)], HIV-associated neurocognitive disorders (HAND) [C1 (Lu et al, 2011), C2 (Cisneros and Ghorpade, 2012), C3 (Persidsky et al, 2000), C4 (Steiner et al, 2006), C5 (Vartak-Sharma et al, 2014)], Huntington’s disease (HD) [D1 (Wang et al, 2013), D2 (Giralt et al., 2010), D3 (Fan and Raymond, 2007)], Multiple Sclerosis (MS) [E1 (Franklin and Kotter, 2008), E2 (Popescu and Lucchinetti, 2012)], Parkinson’s disease (PD) [F1 (Van Spronsen and Hoogenraad, 2010), F2 (Hu et al, 2008), F3 (Zinger et al, 2011), F4 (Niranjan, 2014), F5 (Drinkut et al, 2012), F6 (Ambrosi et al, 2014)], and stroke [G1 (Ceulemans et al, 2010), G2 (Xia et al, 2004), G3 (Lai et al, 2014)].…”

Section: Figmentioning

confidence: 99%

Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

Joshi

Labhasetwar

Ghorpade

2017

J Neuroimmune Pharmacol

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Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of an ideal cellular target, available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability, most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles, are discussed in the context of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analysis of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.

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Astrocyte Elevated Gene-1 Is a Novel Modulator of HIV-1-associated Neuroinflammation via Regulation of Nuclear Factor-κB Signaling and Excitatory Amino Acid Transporter-2 Repression

Cited by 49 publications

References 67 publications

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients

Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery

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