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 host proteins that could contribute to the development of HIV associated dementia and motor complex. In collaboration with Dr. Campbell, we will cross singly tg mice expressing gp120, interleukin-6 (IL-6) or interferon-alpha1 (IFN- alpha1) to generate bigenic mice that express gp120 together with either IL-6 or IFN-alpha1. 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 gp 120 singly tg mice will be compared with those induced in gp 120/hCD4 bigenic mice (engineered to express hCD4 on brain macrophages/microglia). While the coexpression 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 gp 120-induced brain damage. Different strains of gp 120/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 gp 120 tg Balb/cByJ mice to evaluate whether the dwarfism and low blood glucose level that develop in this strain reflect gp 120-induced disturbances of central neuroendocrine circuits. If this postulate is confirmed, this strain/phenotype could provide a useful readout for the assessment of treatments aimed at detrimental HIV-CNS interactions. To determine whether the cerebral expression of detrimental or neuroprotective factors is reflected in alterations of neuronal functions, the mice described above will be analyzed by the Functional Assessment Core in electrophysiological and neurobehavioral paradigms. To further dissect the effects of gp 120/cytokine, gp120/hCD4 and gp 120/hAPP interactions on neurons at the molecular level, experiments in tg mice will be complemented by analyses of neuronal/glial co-cultures. This in vitro analysis will include measurements of intraneuronal calcium levels and electrophysiological responses, as proposed in Dr. Gruol's component. The above experiments are expected to advance our understanding of HIV-1 associated neurological disease and to help identify important targets for therapeutic interventions.
Showing the most recent 10 out of 219 publications
