GPI-1046 protects dorsal root ganglia from gp120-induced axonal injury by modulating store-operated calcium entry

Human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) occurs in a large fraction of patients infected with HIV. Viral components, including the coat protein gp120, are thought to exert toxic actions on dorsal root ganglia (DRG) sensory neurons that can be further exacerbated by treatment of HIV infection with some antiretroviral agents. In a tissue culture model of HIV-SN, we found that gp120-induced axonal degeneration in DRG sensory neurons was prevented by treatment with the immunophilin ligand GPI-1046. Gp120 induced a rapid and large release of endoplasmic reticulum (ER) calcium in DRG neurons that was attenuated by treatment with GPI-1046. Further experiments suggested that GPI-1046 reduced the total ER calcium load by attenuating store-operated calcium (SOC) entry. Together, these results suggest that GPI-1046 protects DRG from gp120-induced axonal damage by decreasing the entry of calcium through SOC, thus reducing the total volume of ER calcium that is available to be released by gp120.