Inhibiting IRE-1 RNase signaling decreases HIV-1 Tat-induced inflammatory M1 state in microglial cells

HIV-1 transactivator (Tat) protein plays a critical role in neurological disorders resulting from viral infection, commonly known as HIV-1-associated neurocognitive disorders (HAND). Previous studies have shown that circulant Tat induces M1 microglial activation, one of the hallmark features of HAND, and this is coupled with ER stress and subsequent Unfolded Protein Response (UPR) triggering. Here, we demonstrate that bystander stimuli of Tat in microglial cells result in the simultaneous overexpression of IRE1-related markers and production of M1-typed proinflammatory mediators. We also show that blocking IRE1/XBP-1 signaling using 4μ8C diminishes such inflammatory response. These findings reinforce a role for the IRE1/XBP-1 pathway in HIV-1 Tat neuropathology and suggest that targeting IRE1 RNase activity using 4μ8C or analogue compounds may provide a therapeutic intervention to mitigate against neuroinflammation in HAND.