HIV-1 Coat Protein Neurotoxicity Prevented by Calcium Channel Antagonists

Abstract

Coat protein gp120 from the human immunodeficiency virus type-1 (HIV-1) increased intracellular free calcium and injured rodent retinal ganglion cells and hippocampal neurons in culture. Highly purified recombinant gp120 envelope protein produced these effects in a dose-dependent fashion at picomolar concentrations. Immunoprecipitation with antibody to gp120, but not with control immunoglobulin-containing serum, depleted solutions of the viral envelope protein and also prevented both the rise in intracellular calcium and neuronal toxicity. The gp120-induced increase in intracellular calcium was abrogated by transiently lowering extracellular calcium or by adding the dihydropyridine calcium channel antagonist nimodipine (100 nM). Calcium channel antagonists also prevented gp120-induced neuronal injury. In addition, intracellular stores appeared to contribute substantially to the increase in calcium elicited by gp120. Since increases in intracellular calcium have been associated with neurotoxicity, it is possible that an injurious effect of gp120 on neurons might be related to this mechanism and that treatment with calcium channel antagonists may prove useful in mitigating HIV-1-related neuronal injury.

HIV-1 gp120 receptor on CD4-negative brain cells activates a tyrosine kinase

“…Recent reports on the neurotoxicity of gp 120 in cell culture suggested that signal transduction through an unknown surface molecule may disturb cellular tunetians by raising intracellular Ca 2 + concentrations ( Brenneman et al, 1988;Dreyer et al, 1990;Kaiser et al, 1990;Pulliam et al, 1991 ). When we measured intracellular Ca 2 + concentrations in D-54 cells in response to 0.01 to 1 J.Lg/ml rgp120, no increase of Ca 2 + Ieveis could be detected (Fig.…”

“…ln AIDS patients, this mechanism has been suggested to be responsible forT helper cell depletion (Ameisen and Caprone, 1 991) and could also cause cellular dysfunction and atrophy as observed in the brain (Fauci, 1988). ln addition, the HIV envelope glycoprotein gp 120 has been shown to increase intracellular Ca 2 + concentrations tagether with NMDA receptor agonists and to injure rodent neurons in vitro (Brenneman et al, 1988;Dreyer et al, 1990;Lipton et al, 1991 ). These mechanisms and the observed tyrosine phosphorylation in response to rgp120 in glial cells could provide a combination of signals leading to astrocytosis, impairment of myelin, and neurodegeneration as found in brains of AIDS patients.…”

“…However, to mediate signals possibly leading to cellular dysfunction, entry of viruses into cells is not necessary, but rather the interaction of HIV-1 or gp 120 with cell surface receptors may be sufficient. lndeed, it was found that treatment of neuronal cultures of rodents with gp120 tagether with exitatory amino acids resulted in marked increases of intracellularcalcium and ultimately in neuronal cell death (Brenneman et al, 1988;Choi, 1988;Dreyer et al, 1990;Kaiser et al, 1990;Lipton et al, 1991 ). Theseobservations give certainly support to the hypothesis that soluble HIV-1 gp120 may interfere not only with neuronal, but also with glial cell functions and may be associated with the development of ADC.…”

“…Manifestations of ADC are progressive cognitive, motor, and behavioral dysfunctions that have been linked to the persistence of HIV-1 infections in the CNS and are mainly found in CD4-positive (CD4+) microglial cells and circulating macrophages (Budka, 1991;Fauci, 1988;Jordan et al, 1991;Ketzler et al, 1990;Liu et al, 1990;Maddon et al, 1986;McArthur, 1987;Merrill and Chen, 1991;Price et al, 1988). However, in the absence of CD4 molecules on the cell membrane of the majority of brain cells and in the light of the paucity of direct evidence for HIV infection of neurons and glial cells it has been suggested that the HIV-associated degenerative neurological abnormalities are the result of indirect mechanisms mediated by soluble factors of viral or cellular origin (Brenneman et a/., 1988;Dreyer et al, 1990;Giulian et al, 1990;Kaiser et al, 1990;Pulliam et al, 1991;Wahl et al, 1991 ). These factors could be cytotoxic to Subpopulations of brain cells or interfere with neuronal and glial cell functions leading to neurodegeneration.…”

Cytokine-Stimulated, But Not HIV-Infected, Human Monocyte-Derived Macrophages Produce Neurotoxic Levels of l-Cysteine

“…This neuronal damage is thought to be predominantly indirect, resulting from the stimulation of macrophages and subsequent release of toxins (9,11,12). The neurotoxic effects of gp120 were demonstrated both in primary rodent and human neuronal cultures and in a gp120-transgenic mouse model (13)(14)(15)(16)(17)(18)(19)(20)(21). Previous studies in our laboratory and in others demonstrated that picomolar concentrations of gp120 cause a dramatic increase in the ability of glutamate to increase intracellular calcium levels and consequent neuronal damage in an "excitotoxic," N-methyl-D-aspartate (NMDA) receptor-mediated fashion (14 -19).…”