Axonal injury is seen in subjects with Human Immunodeficiency Virus type 1 (HIV) associated dementia (HAD). The lack of documented evidence of direct infection of neurons by HIV has prompted studies to reveal possible mechanisms for HIV-mediated axonal damage. However, the nature and the site of initial injury to the neuron are unknown;in particular it is unclear if the process starts in the axons itself or in the neuronal cell body. Several lines of independent investigations have shown that the viral envelope protein gp120 promotes neuronal degeneration. The neurotoxic effect of gp120 occurs through chemokine receptors. Preliminary evidence has shown that the chemokine receptor CXCR4 promotes endocytosis of T-tropic gp120 into neurons. Endocytosis of gp120 is followed by axonal transport through microtubules. The length of axons and survival rate of neurons that do not internalize gp120 is significantly greater when compared to those accumulating gp120. Moreover, agents that block axonal transport are neuroprotective against gp120 even in the presence of cytokines, suggesting that the toxic effect of gp120 may not necessarily require an inflammatory response. Most importantly, gp120 endocytosis and transport precede synaptic simplification and caspase-3 activation and therefore neuronal cell death, suggesting that accumulation and axonal transport of gp120 are crucial to its toxicity. These data lead to a new challenging hypothesis that gp120 binding to CXCR4 receptor initiates a series of events that triggers direct axonal toxicity. However, little is known about the cellular and molecular mechanisms of this effect. Internalized gp120 could cause axonal damage and neuronal apoptosis by affecting axonal proteins or impairing the axonal transport of important molecules that are necessary for neuronal survival and maintenance. The experiments planned in this project will examine whether gp120 affects selected regulatory kinases of axonal transport, or microtubule-associated protein such as Tau, or other cytoskeleton proteins that when impaired, promote the "dying-back" pattern of degeneration. These experiments will be accompanied by histological analysis of gp120 immunoreactivity within endosomes or other cellular organelles, as well as by biochemical analyses of pro-inflammatory cytokines. The ability of gp120 to induce a rapid axonal/dendritic degeneration raises the hypothesis that this protein is sufficient to initiate an irreversible neurodegenerative process even in the absence of other endogenous neurotoxins or other patho-physiological insults. If proven, our hypothesis that gp120 injures neurons by being internalized and transported to their cell bodies will lead to a major discovery in this field. Overall, we expect to provide new significant data that help in the design of adjunct therapies against synaptic simplifications caused by HIV.
Human Immunodeficiency Virus invades the brain and causes degeneration of neurons. Currently, there is no effective therapy to reverse HIV-mediated neuronal degeneration. Key to develop new therapies is the understanding of the mechanisms of HIV neurotoxicity. In this proposal, we will test the hypothesis that the virus promotes degeneration of axons through its envelope protein gp120. This viral protein is internalized into neurons and transported to cell bodies. Neurons internalizing gp120 exhibit short processes and apoptosis. These phenomena are blocked by inhibitors of axonal transport. Therefore, we propose to explore the hypothesis that axonal transport of gp120 is an intracellular mechanism crucial for its neurotoxic effect.
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