Vertical transmission (Mother to child) is the primary mode of HIV-1 infection among young children worldwide, resulting in at least 1700 new infections each day or more than one pediatric infection every minute (UNAIDS/WHO, 1999; 2001). Viral products released by HIV-infected cells cause widespread metabolic derangement as evident in neuronal dysfunction, disruption of neuro-glial relationships, and immune dysregulation, all of which ultimately cause cerebral dysfunction and precipitate the development of HIV dementia. It has been well established that specific proteins encoded by the HIV genome, e.g., Tat and gp120, 1) are neurotoxic, 2) are elevated in brain tissue of patients with HIV dementia, and 3) when presented to the brain in vivo, both proteins cause histological changes that are consistent with those seen in patients with HIV dementia. These data suggest that clinically relevant studies of HIV neuropathogenesis may now be performed in a rodent model. One notable advantage of directly studying the virotoxins is that neuropathogenesis may be studied independent of the virus per se and the complications of secondary infections. The proposed program specifically addresses the major question: What are the neurodevelopmental effects of the HIV proteins Tat and gp120 and how are these effects mediated? Our hypothesis is that: Neonatal exposure to the HIV proteins, Tat and gp120, will produce specific neurodevelopmental disruptions in cognitive processes and that these disruptions will be evident in central catecholamine systems and attributable to interference of key developmental processes. Using a virotoxin exposure model (HIV proteins Tat/gp120) our programmatic studies will determine the adverse effects of these proteins on the developing central nervous system of perinatal animals. Several very important pieces of information will be provided. First, we will identify dose-response functions for the adverse neurobehavioral and neuroanatomical effects of perinatal HIV protein neurotoxicity. Second, we will identify the potential critical periods responsible for the adverse neurobehavioral and neuroanatomical effects of perinatal HIV protein neurotoxicity. Third, these deleterious effects will be identified independent from those of secondary infections, polydrug and/or nutritional interactions that characterize the clinical HIV/AIDS populations. Thus, this project will: A) contribute to our understanding of Tat/gp120 in a clinically relevant rodent model, B) further provide a comprehensive examination of potential catecholamine targets responsible for early developmental disorders independent of secondary opportunistic infections, and C) provide the foundation for an examination of these very same potential mechanisms for HIV protein neurotoxicity in humans with the use of fetal autopsy tissue. ? ?
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