Granulocyte-macrophage colony-stimulating factor enhances viral load in human brain tissue: amelioration with stavudine.

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is elevated in cerebrospinal fluid in HIV- associated dementia; in addition, therapeutic GM-CSF elevates plasma viral load. To assess the effect of GM-CSF on viral replication and the potential ameliorative effect of antiretroviral therapy. A primary human brain aggregate system is used as a model of the in vivo situation. Cultured aggregates were infected with the macrophage tropic strain HIV-1SF162 and then exposed to varying GM-CSF concentrations and 0.3 micromol/l stavudine. Viral replication was assessed by p24 expression in the supernatant and aggregates. Immunohistochemistry identified neurons, astrocytes, microglia and oligodendrocytes. A GM-CSF concentration of 1 ng/ml resulted in a fivefold increase in microglial cells, the main HIV cellular reservoir (P = 0.0001). Prior GM-CSF exposure before infection of the aggregates resulted in sixfold increase in p24 levels compared with non-GM-CSF-exposed infected aggregates. Infected aggregates with or without GM-CSF had significant neuronal loss of 50% and 45%, respectively, and astrocytosis. Addition of stavudine to the infected aggregates, even in the presence of GM-CSF, reduced p24 levels to zero and prevented neuronal loss and astrocytosis. This study demonstrates that GM-CSF enhances viral replication while addition of stavudine prevents this potentially detrimental process.