Human immunodeficiency virus 1 glycoprotein 120 induces endoplasmic reticulum stress in neurons.

People living with Human Immunodeficiency Virus (HIV) (PLWH) may develop HIV-associated neurocognitive disorder (HAND) despite the use of antiretroviral therapy. Therefore, more studies are needed to identify novel therapies, which require a better understanding of the molecular and cellular mechanisms underlying HIV neurotoxicity. The HIV envelope protein gp120 causes neuronal degeneration similar to that observed in HAND. One mechanism contributing to gp120-mediated neurotoxicity may involve its ability to inhibit protein processing in the Golgi apparatus and endoplasmic reticulum (ER). To provide data in support to this hypothesis, we have used a variety of experimental approaches to investigate the effect of gp120 on ER dynamics. We first analyzed the levels of ER stress-associated proteins, such as immunoglobulin heavy chain binding protein (BiP) and phosphorylated Inositol-Requiring Enzyme 1 alpha (p-IRE1α) by western blot, as well as ER morphology by electron microscopy in gp120 transgenic (tg) mice. We found that the hippocampus of gp120tg mice exhibits an increase of BiP levels and p-IRE1α, as well as altered ER morphology when compared to wild type mice. We confirmed that gp120 alters ER morphology in neurons by using rat cortical neurons in culture. The effect of gp120 was chemokine-co-receptor dependent because AMD3100, a CXCR4 receptor antagonist, abolished the effect of gp120 on BiP immunoreactivity. Moreover, using Gluc-ASARTDL, a reporter protein for monitoring ER calcium, and live Ca²⁺ imaging, we show that gp120 induces ER Ca²⁺ depletion in neurons. Overall, our data suggest that gp120 promotes ER stress in neurons.