The underlying mechanisms responsible for HIV-related cognitive and motor deficits, known as AIDS dementia complex (ADC), are probably multi-factorial in nature, as no clear correlation exists between these deficits and pathological measures in this disease. Spontaneous recovery from cognitive deficits and recovery with anti-retroviral therapy indicates that some deficit may have a reversible, non-cytotoxic etiology. We hypothesize that glutamate neurotransmitter-mediated cell signaling ius altered due to the actions of HIV-infected macrophages (MF) on components of signaling; release and uptake of glutamate and glutamate receptors. Specifically, we believe that the lipid mediators (LM) arachidonic acid, platelet activating factor and prostaglandin E2 can cause reversible changes in neurotransmission at the glutamatergic synapse. The goal of the proposed studies is to understand how LM generated under pathological conditions in the HIV-infected brain may alter properties of neurotransmitter transport, release and receptors, leading to changes in glutamatergic cell signaling. We will initially investigate changes in critical LM synthetic enzymes in brains from autopsy of HIV-, HIV+, AIDS, and ADC patients, and establish associations with induction of these enzymes and changes in glutamate transport. Organotypic hippocampal slices from neonatal rat brain co- cultured with HIV-infected human Mf will be used to model the effects of LM on the integrated components of synaptic signaling. We will investigate whether LM are produced in excess in the model system, and whether this LM production affects glutamate uptake, release, receptors and, most importantly, cell signaling. Detailed analyses of changes to glutamatergic cell signaling in neurons will be investigated with electrophysiology and calcium imaging studies. An understanding of possible LM-mediated non-cytotoxic mechanisms of ADC may suggest therapeutic strategies aimed at LM enzymes and receptors. The immune- privileged nature of the brain, paucity of CNS-targeted therapeutics and recent reports of anti-retroviral therapy failures all suggest that HIV- associated cognitive and motor deficits may continue to persist. These findings may be particularly relevant in reducing onset and severity of ADC.
|Nakahara, Haruka; Zhang, Li I; Merzenich, Michael M (2004) Specialization of primary auditory cortex processing by sound exposure in the ""critical period"". Proc Natl Acad Sci U S A 101:7170-4|
|Mahlknecht, U; Deng, C; Lu, M C et al. (2000) Resistance to apoptosis in HIV-infected CD4+ T lymphocytes is mediated by macrophages: role for Nef and immune activation in viral persistence. J Immunol 165:6437-46|
|Herbein, G; O'Brien, W A (2000) Tumor necrosis factor (TNF)-alpha and TNF receptors in viral pathogenesis. Proc Soc Exp Biol Med 223:241-57|