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Figure 4 | AIDS Research and Therapy

Figure 4

From: Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND)

Figure 4

Contribution of the dicysteine motif in Tat to neuropathogenesis. (1) Tat is secreted by infected macrophages and microglia in the vincity of the blood brain barrier resulting in damage to the integrity of the barrier. Dicysteine Tat can act as a ligand on certain chemokine receptors expressed by circulating monocytes (i.e. CCR2, CCR3, CCR5), and promote monocyte migration across the BBB into the CNS [148]. Clade C Tat lacking the intact dicysteine motif fails to attract monocytes in a two chamber migration assay [149]. (2) Dicysteine Tat (TatB but not TatC) also induces higher expression of CCL2 and activation marker CD40 in microglial cells than non-dicysteine Tat [150]. (3) When applied to astrocytes, dicysteine Tat induces higher levels of CCL2 [149] and in HIVE SCID Mouse model astrogliosis is more pronounced in the presence of HIV-1 with an intact dicysteine motif [151]. (4) In neurons, it has been proposed that the Cys31 in the Tat dicysteine motif specifically disrupts the disulfide bond between Cys 744 and Cys 798 on the NR1 subunit of the NMDA receptor, leading to persistent activation of the NMDA receptor [152]. The increase in Tat-mediated apoptosis in dicysteine Tat is also seen in human primary neurons (mediated by increased levels of cleaved caspase-3), in addition to higher levels of ROS and increased levels of mitochondrial depolarization [149]. Primary Human neurons exposed to viral supernatants from HIV-1 with intact dicysteine motif exhibit neuronal apoptosis and HIV-1 SCID mice exposed to the same supernatants have cognitive dysfunction [151].

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