Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research

Thaney, Victoria E.; Sánchez, Ana B.; Fields, Jerel Adam; Minassian, Arpi; Young, Jared W.; Maung, Ricky; Kaul, Marcus

doi:10.1007/s13365-017-0584-2

Cited by 41 publications

(29 citation statements)

References 124 publications

(229 reference statements)

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“…As stated in the regulation of GFAP expression, IL-6 cytokine family member and JAK2/STAT3 cascade can form a positive feedback loop, in which increased GFAP expression during astrogliosis also increases the production of IL-6 cytokine family member, thereby worsening the inflammatory reactions. In addition, GFAP transgenic studies showed that HIV-1 gp120 coater proteins are neurotoxic to the GFAP gene and can cause hydrocephalus in mice (Brenner, 1994) as well as other disorders (Thaney et al, 2018). These findings have been substantiated by clinical observations.…”

Section: Inflammationmentioning

confidence: 88%

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Liu

et al. 2019

Glia

117

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Glial fibrillary acidic protein (GFAP), a type III intermediate filament, is a marker of mature astrocytes. The expression of GFAP gene is regulated by many transcription factors (TFs), mainly Janus kinase‐2/signal transducer and activator of transcription 3 cascade and nuclear factor κ‐light‐chain‐enhancer of activated B cell signaling. GFAP expression is also modulated by protein kinase and other signaling molecules that are elicited by neuronal activity and hormones. Abnormal expression of GFAP proteins occurs in neuroinflammation, neurodegeneration, brain edema‐eliciting diseases, traumatic brain injury, psychiatric disorders and others. GFAP, mainly in α‐isoform, is the major component of cytoskeleton and the scaffold of astrocytes, which is essential for the maintenance of astrocytic structure and shape. GFAP also has highly morphological plasticity because of its quick changes in assembling and polymerizing states in response to environmental challenges. This plasticity and its corresponding cellular morphological changes endow astrocytes the functions of physical barrier between adjacent neurons and stabilizer of extracellular environment. Moreover, GFAP colocalizes and even molecularly associates with many functional molecules. This feature allows GFAP to function as a platform for direct interactions between different molecules. Last, GFAP involves transportation and localization of other functional proteins and thus serves as a protein transport guide in astrocytes. This guiding role of GFAP involves an elastic retraction and extension cytoskeletal network that couples with GFAP reassembling, transporting, and membrane protein recycling machinery. This paper reviews our current understanding of the expression and functions of GFAP as well as their regulation.

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Section: Inflammationmentioning

confidence: 88%

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Liu

et al. 2019

Glia

117

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“…HIV gp120 is a potent neurotoxin (Kim et al, 2011;Meucci and Miller, 1996;Zhou et al, 2017) that has been measured in the brains of patients with HAND (Jones et al, 2000). HIV gp120 evokes synaptic and behavioral deficits in vivo that mimic significant aspects of HAND (Thaney et al, 2018;Toggas et al, 1994). In this study, we used a cell culture model to study changes in tonic inhibition during exposure to the neuroinflammatory stimulus gp120.…”

Section: Introductionmentioning

confidence: 99%

HIV gp120 upregulates tonic inhibition through α5-containing GABAARs

Green

Thayer

2019

Neuropharmacology

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HIV-Associated Neurocognitive disorder (HAND) affects nearly half of infected patients. The HIV envelope protein gp120 is shed by infected cells and is a potent neurotoxin in vitro that reproduces many aspects of HAND when expressed in vivo. Here, we show that HIV gp120 increases the amplitude of a tonic current mediated by γ-aminobutyric acid type-A receptors (GABA A Rs). Treating rat hippocampal cultures with 600 pM gp120 IIIB for 4 h increased a tonic bicucullinesensitive current, which remained elevated for 24 h. The increased current resulted from upregulation of extrasynaptic α5-containing GABA A Rs, as indicated by inhibition with the selective inverse agonist basmisanil. Treatment with gp120 increased α5-GABA A R immunoreactivity on the cell surface without new protein synthesis. The increase in tonic inhibition was prevented by a C-X-C chemokine receptor type 4 (CXCR4) antagonist or elimination of microglia from the culture. Treatment with interleukin-1β (IL-1β) increased the tonic current and an IL-1 receptor antagonist blocked the gp120-evoked response. Pharmacological or genetic inhibition of p38 mitogen-activated protein kinase (MAPK) prevented the gp120-evoked increase in tonic current and direct activation of a mutant form of p38 MAPK expressed in neurons increased the current.

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“…Neurogenesis is important to study in the context of HAND, because HIV-1 virions have been found in the hippocampal formation of pediatric AIDS patients [ 18 ], and impaired neurogenesis has been observed in both HIV-1-infected patients and SIV-infected macaques [ 19 , 20 ], as well as glial fibrillary acidic protein (GFAP)-driven gp120 transgenic mice [ 21 – 25 ] and GFAP-Tat transgenic mice [ 26 , 27 ]. More importantly, NSCs have been shown to be targets of active HIV-1 infection [ 25 , 27 – 32 ].…”

Section: Introductionmentioning

confidence: 99%

Adult neurogenic deficits in HIV-1 Tg26 transgenic mice

Putatunda

Zhang

et al. 2018

J Neuroinflammation

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BackgroundEven in the antiretroviral treatment (ART) era, HIV-1-infected patients suffer from milder forms of HIV-1-associated neurocognitive disorders (HAND). While the viral proteins Tat and gp120 have been shown to individually inhibit the proliferation and neural differentiation of neural stem cells (NSCs), no studies have characterized the effects of all the combined viral proteins on adult neurogenesis.MethodsThe HIV-1 Tg26 transgenic mouse model was used due to its clinical relevance to ART-controlled HIV-1-infected patients who lack active viral replication but suffer from continuous stress from the viral proteins. Quantitative RT-PCR analysis was performed to validate the expression of viral genes in the neurogenic zones. In vitro stemness and lineage differentiation assays were performed in cultured NSCs from HIV-1 Tg26 transgenic mice and their wild-type littermates. Hippocampal neurogenic lineage analysis was performed to determine potential changes in initial and late differentiation of NSCs in the subgranular zone (SGZ). Finally, fluorescent retroviral labeling of mature dentate granule neurons was performed to assess dendritic complexity and dendritic spine densities.ResultsVarying copy numbers of partial gag (p17), tat (unspliced and spliced variants), env (gp120), vpu, and nef transcripts were detected in the neurogenic zones of Tg26 mice. Significantly fewer primary neurospheres and a higher percentage of larger sized primary neurospheres were generated from Tg26 NSCs than from littermated wild-type mouse NSCs, implying that Tg26 mouse NSCs exhibit deficits in initial differentiation. In vitro differentiation assays revealed that Tg26 mouse NSCs have reduced neuronal differentiation and increased astrocytic differentiation. In the SGZs of Tg26 mice, significantly higher amounts of quiescent NSCs, as well as significantly lower levels of active NSCs, proliferating neural progenitor cells, and neuroblasts, were observed. Finally, newborn mature granule neurons in the dentate gyri of Tg26 mice had deficiencies in dendritic arborization, dendritic length, and dendritic spine density.ConclusionsBoth in vitro and in vivo studies demonstrate that HIV-1 Tg26 mice have early- and late-stage neurogenesis deficits, which could possibly contribute to the progression of HAND. Future therapies should be targeting this process to ameliorate, if not eliminate HAND-like symptoms in HIV-1-infected patients.

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Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research

Cited by 41 publications

References 124 publications

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

Neurochemical regulation of the expression and function of glial fibrillary acidic protein in astrocytes

HIV gp120 upregulates tonic inhibition through α5-containing GABAARs

Adult neurogenic deficits in HIV-1 Tg26 transgenic mice

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