The molecular mechanisms responsible for the central nervous system and peripheral nervous system disease associated with HIV infections are not well understood. One possibility is that the exogenous envelope glycoprotein gp12O is released from HIVinfected cells and alters the process of neurotransmission in a manner which adversely affects neural function. gp12O-like activity has been detected in the cerebrospinal fluid (CSF) of cognitively- impaired AIDS patients, indicating that HIV-infected choriod plexus, endothelial, and microglial cells could act as a source of exogenous gp12O in the nervous system. Recently, we obtained some results from a pilot research project funded by the American Foundation for AIDS Research which indicate that exogenous gp12O can affect at least two phenomena in human cells associated with neurotransmission: 1) the induction of the synthesis of the neuromodulatory second messenger molecule, cAMP, by vasoactive intestinal peptide, a neuropeptide found in nerve terminals within the cerebral cortex hippocampus, amygdaloid nucleus and hypothalamus; and 2) the evoked release of catecholamines from cultured human neuron-like cells. We are requesting monies to continue our pilot study which focused on identifying gp12O-induced alterations in the following processes associated with neurotransmission: 1) electrogenic mechanisms, 2) neurotransmitter metabolism, and 3) membrane receptormediated neuromodulatory second messenger synthesis. Specific electrogenic mechanisms to be studied include membrane potentials, capacitances, time constants, action potentials and responses to acetylcholine. Features of neurotransmitter metabolism to be studied include catecholamine content, release, synthesis, and granular storage. The second messengers to be analyzed are the following: cAMP, cGMP, inositol phosphates, diacylglycerol, choline, phosphorylcholine, and phosphatidic acid. In addition, we intend to determine 1) the regions of the gp12O molecule which are responsible for observed effects, and 2) the presence of similar activity in the CSF of AIDS patients. We envision that our observation will lead to additional grant proposals concerning more indepth investigations of gp12O-induced effects. This information can be important for designing therapeutic compounds and strategies for treatment of """"""""neural AIDS.""""""""
