Gp120 induced neurotoxicity – The influence of the chemokine receptor tropism

Degeneration of neurons and astrocytes mediated by soluble viral proteins and neurotoxins is an important factor involved in the pathogenesis of HAD. We investigated whether different soluble HIV-1 envelope proteins (X4, R5 and R5X4 tropic HIV-1 gp120) induced apoptosis in neurons and astrocytes. Here we show that this effect is influenced by the structure and chemokine receptor tropism of the different gp120 isoforms.

We incubated neurons with soluble gp120 proteins differing in the V3 loop for 2h and 4h. Supernatant was added to astrocytes for 24h. Additionally, we blocked neurons with Anti-CXCR4- and Anti-CCR5-Antibodys and incubated the cells in gp120 again for 2h and 4h. Trypan blue and Hoechst-33342 dye was used to determine the percentage of avital cells after the treatment with gp120.

We found that X4-binding gp120 was highly neurotoxic. R5 tropic gp120 also induced apoptosis in neurons but lower. In dual tropic isoforms, this effect depended on the presence of glycosylation at position g17: lacking of glycosylation at this position resulted in a marked reduction of toxicity. The neurotoxic effect of the different gp120 isoforms was blocked depending on the tropism by Anti-CXCR4 and Anti-CCR5 antibodies. Gp120 did not induce apoptosis in astrocytes.

Gp120 induces neurodegeneration depending on its chemokine receptor tropism. In dualtropic isoforms this effect is also depending on glycosylation sites. This might influence the ability of gp120 variants to act as a pathogenetic factor in the development of HAD. Gp120 alters the metabolism of astrocytes but does not induce apoptosis in these cells. Survival of functionally disturbed astrocytes might be another factor involved in the pathogenesis of HAD.