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HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists
E B Dreyer1, P K Kaiser, J T Offermann
1Department of Neurology, Children's Hospital, Boston, MA.
Insights
The human immunodeficiency virus type-1 (HIV-1) coat protein gp120 increases intracellular calcium, causing neuronal injury. Calcium channel blockers may mitigate this HIV-1-related neurotoxicity.
Area of Science:
- Neuroscience
- Virology
- Cell Biology
Background:
- The human immunodeficiency virus type-1 (HIV-1) envelope protein gp120 is implicated in neurological damage.
- Elevated intracellular calcium levels are a known mechanism of neurotoxicity.
Purpose of the Study:
- To investigate the role of gp120 in neuronal calcium dysregulation and toxicity.
- To explore the potential of calcium channel antagonists in preventing gp120-induced neurotoxicity.
Main Methods:
- Primary neuronal cultures (rodent retinal ganglion cells and hippocampal neurons) were exposed to purified recombinant gp120.
- Intracellular calcium levels were measured using calcium imaging.
- Neuronal injury was assessed morphologically.
- The effects of calcium depletion, calcium channel antagonists (nimodipine), and immunoprecipitation were evaluated.
Main Results:
- Recombinant gp120 dose-dependently increased intracellular calcium and caused neuronal injury at picomolar concentrations.
- Antibody to gp120 neutralized these effects, confirming gp120's role.
- Lowering extracellular calcium or adding nimodipine prevented gp120-induced calcium increase and toxicity.
- Intracellular calcium stores significantly contributed to the gp120-elicited calcium rise.
Conclusions:
- HIV-1 gp120 induces neuronal injury by increasing intracellular calcium, potentially through calcium channels and intracellular stores.
- Calcium channel antagonists show promise in mitigating HIV-1-associated neurotoxicity.
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.