A murine model of HIV encephalitis: xenotransplantation of HIV‐infected human neuroglia into SCID mouse brain

Vj, Sanders; Mehta, A; White, Michael G.; Cl, Achim

doi:10.1046/j.1365-2990.1998.00145.x

Cited by 14 publications

(4 citation statements)

References 11 publications

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“…Disease pathogenesis revolves around the continuous ingress of monocytes into the brain with subsequent immune activation and an expanding viral reservoir in brain microglia and perivascular macrophages (Wiley et al, 1991a;Hori et al, 1999;Weiss et al, 1999). A murine model of HIVE was generated to reflect the neurotoxicity and neuropathogenesis of HIV-1 infection (Persidsky et al, 1996;Sanders et al, 1998;Limoges et al, 2000). We confirmed that the histological Figure 6.…”

Section: Discussionsupporting

confidence: 75%

Neuroprotective Activities of Sodium Valproate in a Murine Model of Human Immunodeficiency Virus-1 Encephalitis

et al. 2003

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Human immunodeficiency virus-1 (HIV-1) infection of the nervous system can result in neuroinflammatory events leading first to neuronal dysfunction then to cognitive and behavioral impairments in infected people. The multifaceted nature of the disease process, commonly called HIV-1-associated dementia (HAD), provides a number of adjunctive therapeutic opportunities. One proposed adjunctive therapy is sodium valproate (VPA), an anticonvulsant known to promote neurite outgrowth and increase beta-catenin through inhibiting glycogen synthase kinase 3beta activity and tau phosphorylation. We now show that VPA treatment of rat cortical neurons exposed to HIV-1 gp120 prevents resultant neurotoxic activities. This includes the induction of significant neurite outgrowth and microtubule-associated protein 2 (MAP-2) and neuron-specific nuclear protein (NeuN) antigens in affected neuronal cell bodies and processes. Similarly, VPA protects severe combined immunodeficient (SCID) mice against the neurodegeneration of HIV-1ADA infected monocyte-derived macrophages (MDMs). In SCID mice with HIV-1 MDM-induced encephalitis, VPA treatment significantly reduced neuronal phosphorylatedbeta-catenin and tau without affecting HIV-1 replication or glial activation. We conclude that VPA protects neurons against HIV-1 infected MDM neurotoxicity, possibly through its effects on the phosphorylation of tau and beta-catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.

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Section: Discussionsupporting

confidence: 75%

Neuroprotective Activities of Sodium Valproate in a Murine Model of Human Immunodeficiency Virus-1 Encephalitis

et al. 2003

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“…See Table 1 for statistical comparisons between individual treatments. grafts in the brain of SCID mice have already been dis cussed elsewhere (42). Currently, we have shown that primary cultures of second trimester human fetal brain tissues can be successfully grafted into the striatum of SCID mice, survive for at least 8 months, and that hu man neurons differentiate and may form synapses within the graft.…”

Section: Discussionmentioning

confidence: 93%

Neuron-Enriched Second Trimester Human Cultures: Growth Factor Response and in Vivo Graft Survival

et al. 1999

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Grafts of first trimester fetal tissue show limited survival and integration in the adult CNS. Alternative grafting strategies have been sought for treatment of neurodegenerative disease. We have developed cultures of human second trimester fetal tissues to study neuronal differentiation. Grafted into the SCID mouse striatum, aggregates of these cultures formed neuron-rich xenografts for at least 8 months. We examined the influence of various neurotrophic factors, including basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), transforming growth factor-beta 1 (TGF-beta1), and hepatocyte growth factor (HGF), on the growth and differentiation of neuronal and glial cell populations. BDNF promoted the survival and differentiation of second trimester neurons whereas bFGF exhibited a strong proliferative effect on precursors and the astroglial population. Our data suggest that second trimester human fetal cultures contain neuroprogenitor cells that can be directed to the neuronal lineage. This process may be amplified by treatment with BDNF, which we hypothesize could improve the long-term in vivo survival of neuron-enriched grafts.

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“…Recent reports show that the prevalence of neurocognitive disorders has risen from 30% to 50% of patients infected with HIV [3]. HIV entry into the CNS is reported to take place during early acute infection [4] via infected macrophages, which cross the blood–brain barrier and transport the virus inside the CNS [5]. …”

Section: Introductionmentioning

confidence: 99%

HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia

Mishra

Chhatbar

Singh

2012

J Neuroinflammation

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BackgroundHIV-1 Tat protein is known to be associated with neuroinflammation, a condition that develops in almost half of patients infected with HIV-1. HIV-1 Tat can alter glial neuroprotective functions, leading to neurotoxicity within the CNS. HIV-1 Tat is known to be secreted from productively infected cells and can affect neighboring uninfected cells by modulating cellular gene expression in a bystander fashion.MethodsWe were interested to study whether exogenous exposure to HIV-1 Tat-C protein perturbs the microRNA (miRNA) expression profile of human microglial cells, leading to altered protein expression. We used protein expression and purification, miRNA overexpression, miRNA knockdown, transfection, site-directed mutagenesis, real-time PCR, luciferase assay and western blotting techniques to perform our study.ResultsHIV-1 Tat-C treatment of human microglial cells resulted in a dose-dependent increase in miR-32 expression. We found that tumor necrosis factor-receptor–associated factor 3 TRAF3) is a direct target for miR-32, and overexpression of miR-32 in CHME3 cells decreased TRAF3 both at the mRNA and the protein level. Recovery of TRAF3 protein expression after transfection of anti-miR-32 and the results of the luciferase reporter assay provided direct evidence of TRAF3 regulation by miR-32. We found that the regulation of interferon regulatory factor 3 (IRF3) and IRF7 is controlled by cellular levels of TRAF3 protein in microglial cells, as after overexpression of miR-32 and application of anti-miR-32, expression levels of IRF3 and IRF7 were inversely regulated by expression levels of TRAF3. Thus, our results suggest a novel miRNA mediated mechanism for regulation of TRAF3 in human microglial cells exposed to HIV-1 Tat C protein. These results may help to elucidate the detrimental neuroinflammatory consequences of HIV-1 Tat C protein in bystander fashion.ConclusionHIV-1 Tat protein can modulate TRAF3 expression through miRNA mediated pathway and can change the downstream expression of IRF3 and IRF7. This study demonstrates a novel mechanism of HIV-1 Tat C protein-mediated perturbation of miRNA, resulting in dysregulation of cellular TRAF3.

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A murine model of HIV encephalitis: xenotransplantation of HIV‐infected human neuroglia into SCID mouse brain

Cited by 14 publications

References 11 publications

Neuroprotective Activities of Sodium Valproate in a Murine Model of Human Immunodeficiency Virus-1 Encephalitis

Neuroprotective Activities of Sodium Valproate in a Murine Model of Human Immunodeficiency Virus-1 Encephalitis

Neuron-Enriched Second Trimester Human Cultures: Growth Factor Response and in Vivo Graft Survival

HIV-1 Tat C-mediated regulation of tumor necrosis factor receptor-associated factor-3 by microRNA 32 in human microglia

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