Advances in HAART have provided us with some surprising insights into the molecular events that underlie the pathogenesis and neurologic disease that accompanies HIV-1 infection of the CNS. In particular, significant amelioration of pre-existing neurologic disease in patients with HAART and lack of correlation between numbers of apoptotic neurons and pre-mortem neurologic status suggests that HIV-1 associated neurologic disease may have a component of reversible metabolic encephalopathy. Astrocytes are required for neuronal cell survival and function. Our overall hypothesis, in part based on studies of the previous cycle of this PPG, is that HIV infection of astrocytes and exposure of the cells to gp120 and TNF-alpha made by infected MDM, diminish the neuroprotective and neuroregulatory functions of astrocytes and thereby contributes to sub-lethal metabolic encephalopathy. Since the deleterious effects of HIV on glia are transient and non-cytopathic, reduction in HIV load in the brain by HAART may restore normal functions of astrocytes and reverse neuronal dysfunction. Accurately modeling this in vitro requires different assays than measuring neuronal apoptosis as an endpoint after exposure to HIV-1 neurotoxins. In Project 4 we will investigate the ability of cortical neurons to undergo process (i.e., neurite) outgrowth, express markers for synapses, and establish metabolic activity in pre-synaptic nerve terminals in response to neighboring astrocytes with treated or infected with HIV-1.
The Specific Aims are: 1) To establish conditions for mixed cultures of treated or HIV-1-infected astrocytes and neurons. In this aim, astrocytes will be treated with gp120 constructs or cellular genes identified in Projects 1 and 2 known to disrupt astrocyte function or infected with HIV-1 in vitro, prior to culturing with neurons. Toxicity studies will be performed to identify conditions that will not kill neurons; 2) To quantify the deleterious effects of treated or HIV-1-infected astrocytes on process outgrowth and functional activities of nerve terminals in compartmentalized cultures where neuronal soma and astrocytes are in compartment 1 and neurites migrate through a diffusion barrier to express synaptic markers in compartment 2; 3) To investigate what glial functions contribute to neuronal dysfunction, including glial glutamate transport and glial regulation of the extracellular matrix that provides support to neurites; and 4) Taking advantage of compartmentalized cultures, to investigate a novel hypothesis that altered glial functions in HIV-1 initially dysregulate genes involve with functional activity in the synaptic compartment prior to alterations in the neuronal soma. Results of these studies will be utilized by Project 3 to better model the in vivo effects of HIV-1 infection in astrocytes in SCID mice. The overall goal of this aim is to better understand the precise nature and temporal sequence of molecular events that occur between the neuron and the astrocyte, findings that will ultimately hope us to prevent neurologic disease in the ear of HAART.
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