Neurotrophic activity of monomeric glucophosphoisomerase was blocked by human immunodeficiency virus (HIV-1) and peptides from HIV-1 envelope glycoprotein

Glucophosphoisomerase (GPI), a glycolytic enzyme, was recently described to share 90% sequence homology with neuroleukin, a recently discovered growth factor which promotes motor neuron regeneration in vivo, survival of peripheral and central neurons in vitro, and affects B cell immunoglobulin synthesis. Interestingly, neuroleukin activity was described to be antagonized by the human immunodeficiency virus (HIV-1) envelope glycoprotein (gp120), with which neuroleukin was found to share partial sequence homology. In this study, reduced GPI demonstrated similar activity to neuroleukin in a novel bioassay using human and rat neuroblastoma cell lines. In the presence of reduced GPI, these cells were found to differentiate, in terms of enhanced neurite extension at a reduced proliferation rate. These results demonstrate the existence of a novel growth factor activity of an evolutionary ancient enzyme. The nonreduced commercial form of GPI, probably the dimer, was found to be inactive in this bioassay. Using the neuroblastoma cells model system, we further investigated the significance of the region of homology to HIV-1 envelope glycoprotein (gp120) as the putative binding site of GPI to its receptor on neuronal cells.     

Evidence for a synergistic effect of the HIV-1 envelope protein gp120 and brain-derived neurotrophic factor (BDNF) leading to enhanced expression of somatostatin neurons in aggregate cultures derived from the human fetal cortex

Changes in the expression of somatostatin (SRIF) have been observed in the brains of HIV encephalitis. Since gp120 is thought to play a major role in AIDS-associated abnormalities in the brain, we addressed the question: Does gp120 alter the functional expression of human fetal SRIF neurons in culture and if so, is this effect fetal-age dependent? Aggregate cultures, obtained from cortices of nine fetuses (14.9–20.7 weeks), were exposed for 7 days to BDNF or BDNF+gp120; BDNF induced production of SRIF during the subsequent 24–48 h was assessed. Similar effects of BDNF and gp120 were observed in the 9 brain-cultures. A 7-day exposure to BDNF alone led to a significant increase in SRIF production (p=0.014), whereas exposure to gp120 alone did not. Co-exposure to BDNF and gp120 led to an increase in BDNF-induced SRIF production which was significantly greater than that after BDNF alone (p=0.006). These effects were BDNF- and gp120-dose dependent and they were not accompanied by changes in DNA content of the aggregates nor in lactate dehydrogenase activity in the medium; indicating that gp120 did not lead to a major loss of cell integrity. These results are consistent with a synergistic effect of BDNF and gp120 leading to enhanced functional expression of the signalling pathway(s) mediating BDNF induction of SRIF production; an effect expressed by fetal brains throughout the 2nd trimester of gestation. Thus, this culture system can serve as a model to study the mechanism(s) underlying the early interactions between gp120 BDNF in the developing human brain.