Over half of HIV-infected patients experience HIV-associated neurocognitive disorders (HANDs), however the molecular mechanisms leading to this neuronal dysfunction are still not fully understood. The authors were interested in feline immunodeficiency virus (FIV), which naturally infects cats and shares a simialr structure, cell tropism and pathology with HIV, including wide-ranging neurologic deficits. Therefore they used FIV as a model to characterise the molecular pathways underlying HIV-induced neuronal dysfunction, particularly, synaptic alteration. The authors found that among HIV-induced neuron-damaging products, the HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca2+ activity in neurons and stimulates various pathways that lead to synaptic function damage. They quantified this neuronal Ca2+ activity using intracellular Ca2+ imaging in cultured hippocampal neurons and were able to confirm that FIV envelope glycoprotein gp95 also also elevates neuronal Ca2+ activity. In addition, gp95 was found to interact with the chemokine receptor CXCR4 and facilitate the release of intracellular Ca2+ by the activation of the endoplasmic reticulum (ER)-associated Ca2+ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. Therefore it appears that HIV gp120 and FIV gp95 share a core pathological process in neurons. The stimulation of NMDARs by gp95 activates cGMP-dependent protein kinase II (cGKII) by activating the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca2+ release from the ER and promotes surface expression of AMPA receptors, in turn leading to an increase in synaptic activity. When feline hippocampal neurons were cultured, the authors found that gp95-induced neuronal Ca2+ overactivation is mediated by both CXCR4 and cGKII. Finally, cGKII activation was also required for HIV gp120-induced Ca2+ hyperactivation. Therefore these findings suggest a neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.
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