The molecular mechanisms of neuronal dysfunction in HIV-1 dementia are not known. However, it is not due to direct HIV infection of neurons. Various viral proteins have been implicated including, the HIV-1 coat protein, gp160, which is cleaved into gp120 and gp41. gp120 is degraded whereas gp41 remains membrane bound. In human postmortem tissue we observe a correlation between expression of gp41, TNFa, iNOS and severe dementia. In juvenile macaques infected with SIV we observe apoptotic cells and expression of gp41 and iNOS in animals with neurologic disease. We have in vitro evidence that gp41 induces the expression of immunologic nitric oxide synthase (iNOS) resulting in neurotoxicity in wild-type cultures but not in cultures from TNFRp55 null or iNOS null mice. These data suggest that gp41 initiates a neuro-cytokine responses in the brain resulting in NO production, neuronal dysfunction and toxicity. Elevations in the cytokine TNFa have consistently correlated with HIV-1 dementia and TNFa can participate in the induction of iNOS. Is there a connection between gp41, TNFa and iNOS in HIV-1 dementia? To critically examine this hypothesis and characterize this mechanism we propose the following specific aims: (1) Does TNFa contribute to gp41 neurotoxicity? (2) What are the epitopes of gp41 which induce TNFa? (3) Does gp41 induces caspase activation? (4) Does gp41 exposure activated NFkappaB? (5) Are the alterations in the neuro-cytokine pathways identified in vitro present in postmortem tissue from patients with HIV Dementia? In the patient cohort examined to date, gp41 and iNOS expression correlated with rapidly progressing and severe dementia. This series of experiments is designed to determine whether gp41 is a trigger which activates TNFa dependent pathways leading to expression of iNOS and apoptosis. Identification of the target molecules and biochemical pathways which mediated gp41 neurotoxicity will provide new targets for the design of rationale therapy for the treatment of HIV dementia.