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


OBJECTIVE
To assess the effect of GM-CSF on viral replication and the potential ameliorative effect of antiretroviral therapy.


METHODS
A primary human brain aggregate system is used as a model of the in vivo situation.


METHODS
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.


RESULTS
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.


CONCLUSIONS
This study demonstrates that GM-CSF enhances viral replication while addition of stavudine prevents this potentially detrimental process.
Kandanearatchi
Apsara
A
Institute of Psychiatry, King's College, DeCrespigny Park, London SE5 8AF, UK.
Zuckerman
Mark
M
Smith
Melvyn
M
Vyakarnam
Annapurna
A
Everall
Ian P
IP
D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001483:Base Sequence; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D046508:Culture Techniques; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000821:virology; D011994:Recombinant Proteins; D018119:Stavudine / Q000008:administration & dosage / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D004279:DNA, Viral; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018119:Stavudine