Caspase Cascades in Human Immunodeficiency Virus-Associated Neurodegeneration

Abstract

Many patients infected with human immunodeficiency virus-1 (HIV-1) develop a syndrome of neurologic deterioration known as HIV-associated dementia (HAD). Neurons are not productively infected by HIV-1; thus, the mechanism of HIV-induced neuronal injury remains incompletely understood. Several investigators have observed evidence of neuronal injury, including dendritic degeneration, and apoptosis in CNS tissue from patients with HAD. Caspase enzymes, proteases associated with the process of apoptosis, are synthesized as inactive proenzymes and are activated in a proteolytic cascade after exposure to apoptotic signals. Here we demonstrate that HAD is associated with active caspase-3-like immunoreactivity that is localized to the soma and dendrites of neurons in affected regions of the human brain. Additionally, the cascade of caspase activation was studied using an in vitro model of HIV-induced neuronal apoptosis. Increased caspase-3 proteolytic activity and mitochondrial release of cytochrome c were observed in cerebrocortical cultures exposed to the HIV coat protein gp120. Specific inhibitors of both the Fas/tumor necrosis factor-alpha/death receptor pathway and the mitochondrial caspase pathway prevented gp120-induced neuronal apoptosis. Caspase inhibition also prevented the dendrite degeneration observed in vivo in transgenic mice with CNS expression of HIV/gp120. These findings suggest that pharmacologic interventions aimed at the caspase enzyme pathways may be beneficial for the prevention or treatment of HAD.

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

“…The number of neurons was quantified by immunostaining for the neuron-specific markers microtubule-associated protein-2 (MAP-2) and NeuN, and apoptotic nuclei were identified morphologically after staining nuclei with the DNA dyes Hoechst 33342 or propidium iodide. 11,12 In two out of three experiments shown in Figure 1 and in seven out of twenty-seven experiments performed with the different WT and chemokine receptor-deficient murine cerebrocortical cultures, TUNEL (Apoptosis Detection System/Fluorescein, Promega, Madison, WI, USA) was applied to detect fragmented nuclear DNA in apoptotic nuclei. 11,31 Neuronal survival was calculated from the percentage of neurons remaining after subtraction of those that had undergone apoptosis.…”

“…Nuclear DNA was stained with H33342. Deconvolution microscopy was performed as described earlier 12 ; filters for AMCA, CY3, CY5 and FITC were used for four-color image capture and a 'nearest neighbor' algorithm for deconvolution (Slidebook software, Intelligent Imaging Innovations, Denver, CO, USA).…”

Mechanisms of apoptosis induction by the HIV-1 envelope

“…Gp120 also causes neuronal dysfunction and death in rodents in vivo. 40 Specific inhibitors of both the Fas/tumor necrosis factor-a/ death receptor pathway and the mitochondrial caspase pathway can reduce the gp120-induced neuronal apoptosis. 40 When added to mixed cultures of murine neurons and glial cells, gp120 only causes apoptosis when such cells are derived from p53-expressing mice.…”

“…40 Specific inhibitors of both the Fas/tumor necrosis factor-a/ death receptor pathway and the mitochondrial caspase pathway can reduce the gp120-induced neuronal apoptosis. 40 When added to mixed cultures of murine neurons and glial cells, gp120 only causes apoptosis when such cells are derived from p53-expressing mice. Reconstitution experiments in which p53 þ / þ and p53 À/À neurons and glial cells were mixed demonstrated that both cell types (neuronal þ glial) were required for the lethal response to gp120 and that both of them had to express p53 so that neurons would die upon gp120 addition.…”

Potentiation of excitotoxicity in HIV-1-associated Dementia and the significance of glutaminase

“…In a disease of chronic inflammation, incremental stages of increasing stress do not immediately overwhelm a cell's capacity to respond, the stress required to overwhelm cellular repair and homeostatic mechanisms compromise synaptic function long before the induction of cell death mechanisms. In HAD, damage to dendritic arbors and reduction in synaptic density are important neuropathological signatures of HIVE (111,112). This type of damage to the neural network is thought to be an early event in the pathway leading to neuronal dropout via apoptosis (55,113).…”