HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway

Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model

“…Then, cells were treated with purified brain homogenates of Dox-treated iTat mice and the luciferase activity was determined. Based on the luciferase activity, Tat protein expression levels in the brains of Dox-treated iTat mice were calculated to be in the range of 1–5 ng/ml (Fan et al 2016) (Fig. 1c), which is indeed close to the reported Tat levels in the brains of HIV-infected individuals (Fan et al 2016; Westendorp et al 1995; Xiao et al 2000).…”

“…However, it is still unclear whether Tat is present in the CNS or cerebrospinal fluid in HIV-infected individuals at sufficient concentrations to directly cause acute neurotoxicity that is observed in the transgenic models. However, the GFAP-driven expression of Tat protein by astrocytes in the brains of iTat mice was close to actual levels in the brains of HAND patients (Fan et al 2016; Westendorp et al 1995; Xiao et al 2000). In vitro cell culture and in vivo studies show that HIV infects astrocytes, but the contribution that this population of cells makes to HAND is unclear (Jaeger and Nath 2012; Kramer-Hammerle et al 2005).…”

“…Homozygous genotypes were confirmed by crossbreeding transgenic mice with wild-type C57/BL6 mice. After successfully obtaining four iTat mouse lines with expression levels from low to high (Kim et al 2003), an iTat line with Tat expression levels close to that of HIV-infected brains was maintained (Fan et al 2016; Westendorp et al 1995; Xiao et al 2000) and used in subsequent studies and distributed to many other laboratories.…”

“…Given the recent findings that Tat is persistently expressed in the brain of HIV-infected individuals treated with cART (Johnson et al 2013), it was imperative to determine the effects of Tat expression on neurogenesis and HIV-associated minor cognitive motor disorder (MCMD). Taking advantage of the iTat mice, researchers showed that Tat inhibited NPC proliferation and migration and altered NPC differentiation to favor astrogliogenesis over neurogenesis through Tat binding to Notch signaling factors (Fan et al 2016) (Fig. 6).…”

“…Treatment of conditioned medium of Tat-expressing astrocytes with anti-cathepsin B antibody led to marked decreases in the neurotoxicity of Tat-expressing astrocytes (Fan and He 2016b). Notch signaling inhibitor greatly improved Tat-impaired NPC differentiation and neurogenesis in iTat mice (Fan et al 2016). miR-132 inhibitor inhibits astrocyte-derived Tat neurotoxicity, specifically neuron dendritic damage and loss of and synapse formation (Rahimian and He 2016b).…”