HIV-1 associated impairments of cognition and motor performance can culminate in dementia and paralysis. Here we propose to use transgenic (tg) mice, engineered to express pathogenetic factors in their central nervous system (CNS), to study interactions between viral and hot proteins that could contribute to the development of HIV associated dementia and motor complex. Lines of singly tg mice expressing gp120 or interleukin-6 (IL-6) will be crossed to generate bigenic mice that co-express gp120 and IL-6 in their CNS. Brains from bigenic and singly tg will be compared in a well established battery of neuropathological and molecular analyses to assess whether co-expression of gp120 and cytokines enhances/alters the brain damage observed when these factors are expressed individually. This scenario is relevant to HIV-1 encephalitis in which inflammatory responses lead to the co-expression of viral products and cytokines. To evaluate the neuropathogenic potential of interactions between gp120 and the human CD4 receptor (hCD4), CNS alterations of gp120 singly tg mice will be compared with those induced in gp120/hCD4 bigenic mice (engineered to express hCD4 on brain macrophages/microglia). While the co-expression of cytokines or hCD4 may enhance gp120 induced neurotoxicity, we have found that neuronal overexpression of the human amyloid precursor protein (hAPP) can effectively prevent gp120-induced brain damage. Different strains of gp120/hAPP bigenic mice will be generated and analyzed to determine whether this neuroprotective effect is due primarily to hAPP-mediated stabilization of the neuronal calcium homeostasis or to other hAPP effects. We also plan to examine the hypothalamic-pituitary axis of gp120 tg Balb/cByJ mice to evaluate whether the dwarfism and low blood glucose level that develop in this strain reflect gp120-induced disturbances of central neuroendocrine circuits. If this postulate is confirmed, this stain/phenotype could provide a useful readout for the assessment of treatments aimed at detrimental HIV-CNS interaction. To further dissect he effects of gp120/cytokine, gp120/hCD4 and gp120/hAPP interactions on neurons at the molecular level, experiments in tg mice will be complemented by analyses of neuronal/glial co-cultures. The above experiments can be expected to advance our understanding of HIV-1 associated neurological disease and to help identify important targets for therapeutic interventions.
