Simian Immunodeficiency Virus Encephalitis in the White Matter and Degeneration of the Cerebral Cortex Occur Independently in Simian Immunodeficiency Virus-Infected Monkey

Xing, Hui; Moritoyo, Takashi; Mori, Kazuyasu; Tadakuma, Kei; Sugimoto, Chie; Ono, Fumiko; Hayakawa, Hitoshi; Izumo, Shuji

doi:10.1080/713831594

Cited by 4 publications

(17 citation statements)

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“…Our previous study demonstrated astrocyte damage, such as swelling of astrocytic processes and focal or diffuse gliosis in the frontal cortex of SIVmac239‐infected macaques #627, 532 and 682 by electron microscopy . We further found astrocytic processes filled with dense bundles of glial fibrils (Fig.…”

Section: Resultssupporting

confidence: 56%

“…We have previously described clinical and histopathologic findings of four SIVmac239‐infected rhesus macaques, #532, 627, 682, 730, and three SHIV‐RT‐infected rhesus macaques, #631, 677 and 700 . The cerebral cortex, especially frontal cortex, of these animals showed degenerative changes such as diffuse gliosis, apoptosis of astrocytes, and diffuse activation of microglia.…”

Section: Resultsmentioning

confidence: 98%

“…This virus is highly pathogenic and induces AIDS when inoculated intravenously into macaques . The molecularly cloned SIVmac239 and a chimeric virus SHIV‐RT were previously reported …”

Section: Methodsmentioning

confidence: 99%

“…We used EnVision system (DAKO, Copenhagen, Denmark) for immunohistochemistry of neuron‐specific nuclear protein (NeuN) (dilution 1:200; Millipore, Darmstadt, Germany) and GFAP (dilution 1:100; Chemicon International, Temecula, CA, USA). The immunohistochemistry of the EnVision system was previously reported …”

Section: Methodsmentioning

confidence: 99%

“…Using antiretroviral therapy (ART) has significantly decreased the prevalence of HAD, which is the severest form of HAND, but the overall prevalence of HAND and associated morbidity remain high (~50%) . The histopathology of HAND includes chronic brain inflammation and progressive cortical degeneration, such as neuronal loss and apoptosis, synaptic and dendritic simplification and brain atrophy, and we previously reported that these two pathologic events occur independently in a macaque‐AIDS model as well as HIV‐infected individuals . HIV encephalitis can be explained as an inflammatory response against virus‐infected microglia/macrophages in the central nervous system (CNS); however, pathogenesis of the other event, cortical degeneration, is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Decrease of aquaporin‐4 and excitatory amino acid transporter‐2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV‐associated neurocognitive disorders

et al. 2016

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Human immunodeficiency virus (HIV) encephalitis and degeneration of cerebral cortex are established histopathologies of HIV-associated neurocognitive disorders (HAND). We previously reported decreased excitatory amino acid transporter-2 (EAAT-2) and astrocytic apoptosis in cortical degeneration using SIVmac239 and simian-human immunodeficiency virus (SHIV)-infected macaques and human AIDS autopsy cases. In the present study, we added highly pathogenic SIVsm543-3-infected macaques. These animals showed similar degenerative changes in the frontal cortex. Using 11 SIV-infected macaques, three SIVsm543-3, five SIVmac239 and three SHIV, we compared brain pathology caused by three different viruses and further analyzed the pathogenic process of HAND. We noticed vacuolar changes in perivascular processes of astrocytes by electron microscopy, and examined expression of astrocyte-specific protein aquaporin-4 (AQP4) by immunohistochemistry. APQ4 was diffusely positive in the neuropil and perivascular area in control brains. There was patchy or diffuse decrease of AQP4 staining in the neuropil of SIV-infected macaques, which was associated with EAAT-2 staining by double immunostaining. A quantitative analysis demonstrated significant positive correlation between areas of AQP4 and EAAT-2. Some astrocytes express EAAT-2 but not AQP4, and decrease of EAAT-2 expression tended to be less than the decrease of AQP4. Active-caspase-3 immunostaining demonstrated apoptosis of neurons and astrocytes in the area of AQP4/EAAT-2 reduction. These results suggest that AQP4 is damaged first and decrease of EAAT-2 may follow in pathogenesis of cortical degeneration. This is the first demonstration of decrease of AQP4 and its association with EAAT-2 decrease in AIDS brain, suggesting a role in the pathogenesis of HAND.

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Section: Resultssupporting

confidence: 56%

Section: Resultsmentioning

confidence: 98%

“…This virus is highly pathogenic and induces AIDS when inoculated intravenously into macaques . The molecularly cloned SIVmac239 and a chimeric virus SHIV‐RT were previously reported …”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Decrease of aquaporin‐4 and excitatory amino acid transporter‐2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV‐associated neurocognitive disorders

et al. 2016

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Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8‐depleted rhesus macaques: proton MRS imaging at 3 T

Tal

Kirov

et al. 2013

NMR in Biomedicine

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To test the hypotheses that global decreased neuro-axonal integrity reflected by decreased N-acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo-inositol (mI), present in a CD8-depleted rhesus macaque model of HIV-associated neurocognitive disorders. To this end we performed quantitative MRI and 16×16×4 multivoxel proton MR spectroscopic imaging (TE/TR=33/1400 ms) in 5 macaques pre- and 4-6 weeks post-simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM, WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm3 spatial resolution over ~35% of the brain) using linear regression. Pre- to post-infection global WM NAA declined 8%: 6.6±0.4 to 6.0±0.5 mM (p=0.05); GM Cho declined 20%: 1.3±0.2 to 1.0±0.1 mM (p<0.003); global mI increased 11%: 5.7±0.4 to 6.5±0.5 mM (p<0.03). Global, GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest possible GM host immune response.

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HIV-1 Tat increases BAG3 via NF-κB signaling to induce autophagy during HIV-associated neurocognitive disorder

Dong

Xiang

et al. 2018

Cell Cycle

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The human immunodeficiency virus-1 (HIV-1) regulatory protein Tat plays an important role during HIV-1-associated neurocognitive disorders (HAND) by inducing neuronal autophagy. In this study, we used immunohistochemistry, immunofluorescence, western blot, qRT-PCR, and RNA interference to elucidate the involvement of Bcl-2-associated athanogene 3 (BAG3) in the pathogenesis of HIV-1 Tat-induced autophagy during HAND. We found that BAG3 expression is elevated in astrocytes in frontal cortex of macaques infected with simian immunodeficiency virus-human immunodeficiency chimeric virus (SHIV). In addition, in human primary glioblastoma cells (U87), HIV-1 Tat upregulated BAG3 in an NF-κB-dependent manner to induce autophagy. Importantly, suppression of BAG3 or inhibition of NF-κB activity reversed the HIV-1 Tat-induced autophagy. These results indicate that HIV-1 Tat induces autophagy by upregulating BAG3 via NF-κB signaling, which suggests BAG3 and NF-κB could potentially serve as novel targets for HAND therapies.

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Simian Immunodeficiency Virus Encephalitis in the White Matter and Degeneration of the Cerebral Cortex Occur Independently in Simian Immunodeficiency Virus-Infected Monkey

Cited by 4 publications

References 0 publications

Decrease of aquaporin‐4 and excitatory amino acid transporter‐2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV‐associated neurocognitive disorders

Decrease of aquaporin‐4 and excitatory amino acid transporter‐2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV‐associated neurocognitive disorders

Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8‐depleted rhesus macaques: proton MRS imaging at 3 T

HIV-1 Tat increases BAG3 via NF-κB signaling to induce autophagy during HIV-associated neurocognitive disorder

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