Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-related Dementia (AIDSD). These patients exhibit a broad spectrum of motor impairments and cognitive deficits, which follow or parallel cellular loss, atrophy and morphological changes in their brains. The viral envelope glycoprotein gp120 has been suggested to be one of the causal agents of neuronal loss observed in these patients. However, little is known about the molecular and cellular mechanism(s) of the neurotoxic effect of gp120. Data from a previous proposal have established that gp120 causes neuronal cell death by activating an apoptotic pathway through the chemokine receptor CXCR4. Interestingly, the neurotrophin brain-derived neurotrophic factor (BDNF) prevents gp120-mediated neurotoxicity in vitro by decreasing CXCR4 levels. These data lead to the overall hypothesis that BDNF may reduce gp120 toxicity also in vivo. We propose to study the molecular and cellular mechanisms whereby BDNF blocks gp120 neurotoxicity and the involvement of CXCR4. In particular, we plan to examine the role of CXCR4 in gp120-mediated toxicity in vivo by injecting gp120IIIB into the lateral ventricle of rats and comparing its toxic activity with that of gpBal, a strain of gp120 that binds to the chemokine receptor CCR5. We propose to analyze apoptosis by immunohistochemical and biochemical assessment of activated caspase-3 and caspase-9, two proteases that play a crucial role in the apoptotic pathway. These studies will be accompanied by experiments aimed at establishing the molecular and cellular mechanisms whereby BDNF regulates CXCR4 expression. We propose to use BDNF heterozygous (+/-) mice and cerebellar granule cells in culture. In these studies, we will test the hypothesis that BDNF is neuroprotective against gp120 because of its ability to reduce the expression of CXCR4 or increase its internalization. CXCR4 expression will be determined by histological and biochemical detection of CXCR4 immunoreactivity and mRNA, and CXCR4 internalization will be monitored by quantifying beta-arrestin- mediated endocytosis. Moreover, we propose to establish whether BDNF, infused in the lateral ventricle or by recombinant adeno-associated virus, impairs the ability of gp120 to induce apoptosis. Overall, the results of the present study 1) will provide a major break-through on the mechanisms whereby gp120 causes neuronal cell death and the related morphological alterations that may account for the motor and cognitive deficits found in human AIDSD, and 2) will explore the significance of endogenous and exogenous BDNF in the development of a new therapeutic approach for HIV-1-related neurodegenerative diseases.
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