Human immunodeficiency virus (HIV)-1 infection of the central nervous system occurs in the vast majority of HIV infected patients. HIV-associated dementia (HAD) represents the most severe form of HIV-related neuropsychiatric impairment and is associated with neuropathology involving HIV proteins and activation of proinflammatory cytokine circuits. Interferon-γ (IFN-γ) activates the JAK/STAT1 pathway, a key regulator of inflammatory and apoptotic signaling, and is elevated in brains of HIV-1 infected brains progressing to HAD. Recent reports suggest that green tea derived (-)-epigallocatechin-3-gallate (EGCG) can attenuate neuronal damage mediated by this pathway in conditions such as brain ischemia. In order to investigate the therapeutic potential of EGCG to mitigate the neuronal damage characteristic of HAD, IFN-γ was evaluated for its ability to enhance well-known neurotoxic properties of HIV-1 proteins gp120 and Tat in primary neurons and mice. Indeed, IFN-γ enhanced the neurotoxicity of gp120 and Tat via increased JAK/STAT signaling. Additionally, primary neurons pretreated with a JAK1 inhibitor or those derived from STAT1-deficient mice were largely resistant to the IFN-γ enhanced neurotoxicity of gp120 and Tat. Moreover, EGCG treatment of primary neurons from normal mice reduced IFN-γ enhanced neurotoxicity of gp120 and Tat, while attenuating JAK/STAT1 pathway activation. EGCG was also found to attenuate the neurotoxic properties of HIV-1 proteins in the presence of IFN-γ in vivo. Taken together, these data suggest that EGCG attenuates the neurotoxicity of IFN-γ augmented neuronal damage from HIV-1 gp120 and Tat both in vitro and in vivo. Thus EGCG ‡