Acquired immune deficiency syndrome (AIDS) is the ninth leading cause of death in children and is often accompanied by extensive neurological damage. Human immunodeficiency virus type-1 (HIV-1)-associated neurologic disease is more prevalent in children than in adults. The increasing incidence of AIDS in women has been accompanied by an increased frequency of AIDS in infants and children, especially those born to drug abusing mothers. In HIV+ pediatric patients, neurological deficits have been shown in gross motor development, fine motor development, language acquisition and social contacts. Currently, very little is known about fetal exposure to HIV-1 and the factors involved in promoting neurological damage. We have previously demonstrated that the HIV-1 coat protein, gp120, induces neurotoxicity in cultured midbrain dopamine neurons by examining various indices of dopaminergic function. Since our observations were made in a developing neuronal system, the results may be particularly relevant to infants with AIDS, where the neurological effects are so severe. We propose to extend these studies by examining other indices of neurotoxicity, including tyrosine hydroxylase activity, dopamine cell morphology, and DNA fragmentation (an indicator of apoptosis). Additionally, we will determine if stimulants, which have a direct impact on dopaminergic systems, can influence the onset or degree of neuronal damage induced by gp120. This would be relevant for the immature fetal brain and may be an important factor in seropositive drug abusing mothers. Nitric oxide (NO) is known to promote some of the injurious effects of gp120, and we propose to examine the source of nitric oxide as well as measure NO production. Glial cells also represent an important source of neurotoxic mediators and we propose to examine the role of midbrain astrocytes in promoting the neuronal damage induced by gp120 by assessing amino acid efflux, which will indicate whether there are alterations in normal astrocyte physiology. While multifaceted, these studies represent an attempt to identify specific neurotoxic mediators of gp120 which is essential for the development of neuroprotective therapies for HIV-infected infants.
