Impaired Astrocytes and Diffuse Activation of Microglia in the Cerebral Cortex in Simian Immunodeficiency Virus-Infected Macaques Without Simian Immunodeficiency Virus Encephalitis

Xing, Hui; Mori, Kazuyasu; Sugimoto, Chie; Ono, Fumiko; Izumo, Kimiko; Kuboda, Ryuji; Izumo, Shuji

doi:10.1097/nen.0b013e3181772ce0

Cited by 12 publications

(35 citation statements)

References 42 publications

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“…Six macaques ( #1-6 ) were infected with SHIV -SF162.P4 that was inserted the HIV-related genes, and three macaques ( #7-9 ) were infected with SIV sm543-3 . These two virus strains made rhesus macaques to appear similar brain pathological changes with previous SIVmac239-infected rhesus macaques [10, 22–23]. Four macaques ( #10-13) were used as controls.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous research, we reported glial and neuronal apoptosis in the frontal cortex of SIV-infected macaques using TUNEL and ssDNA immunostaining assays [10]. In the present study, we used different viral strains that have similar pathological features compared with previous SIVmac239 [10, 22–23].…”

Section: Resultsmentioning

confidence: 99%

“…In the present study, we used different viral strains that have similar pathological features compared with previous SIVmac239 [10, 22–23]. In the SHIV -SF162.P4 and SIV sm543-3 - infected macaques, gliosis was observed in cortical layers II–V using IHC against GFAP (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Our animals developed systemic AIDS and showed high viral loads in their plasma. There was no correlation between viral RNA load in plasma and pathological changes in cerebral cortical of SIVmac239 and SHIV-RT-infected rhesus macaques using ISH or by the polymerase chain reaction detection of SIV genomes of extracted DNA from microdissected tissue samples [10, 22–23]. In the present study, we have compared the cortical changes of two new different SIV virus, SHIV-162.P4 and SIV sm543-3 .…”

Section: Discussionmentioning

confidence: 99%

“…The histopathological evidences of HAND in the cerebral cortex are characterized as neuronal loss [5–7] and neuronal apoptosis [8–9]. In a previous study, we observed that apoptosis played a role in HAND in a macaque-AIDS model and in human AIDS [10–11]. However, it remains unclear that how neuronal apoptosis contributes to the pathogenesis of HIV-1-associated brain damage.…”

Section: Introductionmentioning

confidence: 99%

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Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells

Wang

Zhang

et al. 2017

Oncotarget

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The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells

Wang

Zhang

et al. 2017

Oncotarget

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Transient acidification and subsequent proinflammatory cytokine stimulation of astrocytes induce distinct activation phenotypes

Renner¹,

Sansing²,

Inglis³

et al. 2013

Journal Cellular Physiology

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The foot processes of astrocytes cover over 60% of the surface of brain microvascular endothelial cells, regulating tight junction integrity. Retraction of astrocyte foot processes has been postulated to be a key mechanism in pathology. Therefore, movement of an astrocyte in response to a proinflammatory cytokine or even limited retraction of processes would result in leaky junctions between endothelial cells. Astrocytes lie at the gateway to the CNS and are instrumental in controlling leukocyte entry. Cultured astrocytes typically have a polygonal morphology until stimulated. We hypothesized that cultured astrocytes which were induced to stellate would have an activated phenotype compared with polygonal cells. We investigated the activation of astrocytes derived from adult macaques to the cytokine TNF-α under resting and stellated conditions by four parameters: morphology, intermediate filament expression, adhesion, and cytokine secretion. Astrocytes were stellated following transient acidification; resulting in increased expression of GFAP and vimentin. Stellation was accompanied by decreased adhesion that could be recovered with proinflammatory cytokine treatment. Surprisingly, there was decreased secretion of proinflammatory cytokines by stellated astrocytes compared with polygonal cells. These results suggest that astrocytes are capable of multiple phenotypes depending on the stimulus and the order stimuli are applied.

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The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

2020

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Purpose of Review Perinatal HIV-1 infection is associated with an increased risk for neurologic impairments. With limited access to clinical specimens, animal models could advance our understanding of pediatric central nervous system (CNS) disease and viral persistence. Here, we summarize current findings on HIV-1 CNS infection from nonhuman primate (NHP) models and discuss their implications for improving pediatric clinical outcomes. Recent Findings SIV/SHIV can be found in the CNS of infant macaques within 48 h of challenge. Recent studies show an impermeable BBB during SIV infection, suggesting neuroinvasion in post-partum infection is likely not wholly attributed to barrier dysfunction. Histopathological findings reveal dramatic reductions in hippocampal neuronal populations and myelination in infected infant macaques, providing a link for cognitive impairments seen in pediatric cases. Evidence from humans and NHPs support the CNS as a functional latent reservoir, harbored in myeloid cells that may require unique eradication strategies. Summary Studies in NHP models are uncovering early events, causes, and therapeutic targets of CNS disease as well as highlighting the importance of age-specific studies that capture the distinct features of pediatric HIV-1 infection.

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Impaired Astrocytes and Diffuse Activation of Microglia in the Cerebral Cortex in Simian Immunodeficiency Virus-Infected Macaques Without Simian Immunodeficiency Virus Encephalitis

Cited by 12 publications

References 42 publications

Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells

Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells

Transient acidification and subsequent proinflammatory cytokine stimulation of astrocytes induce distinct activation phenotypes

The Brain Retains: Nonhuman Primate Models for Pediatric HIV-1 in the CNS

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