Taken together, our data demonstrated that the upregulation of P2Y4R signal both in mice and in activated human astrocytes by Tat regulates the production of inflammatory cytokines and chemokines as well as ATP in astrocytes and in mice via triggering the PI3K/Akt and ERK pathways, which is responsible for HAND process. Here, AKT1 is linked to HIV-associated neurocognitive disorder.