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*
AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129;
New England Regional Primate Research Center, Harvard Medical School, Southboro, MA 01772; and
Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
Chemokines are believed to play a role in the neuropathogenesis of
AIDS through their recruitment of neurotoxin-secreting, virally
infected leukocytes into the CNS. Levels of chemokines are elevated in
brains of patients and macaques with HIV/SIV-induced encephalitis. The
chemokine receptors CCR3, CCR5, and CXCR4 are found on subpopulations
of neurons in the cortex of human and macaque brain. We have developed
an in vitro system using both macaque and human fetal neurons and
astrocytes to further investigate the roles of these receptors in
neuronal response to inflammation. Here we report the presence of
functional HIV/SIV coreceptors CCR3, CCR5, and CXCR4 on fetal human and
macaque neurons and CCR5 and CXCR4 on astrocytes immediately ex vivo
and after several weeks in culture. Confocal imaging of immunostained
neurons demonstrated different patterns of distribution for these
receptors, which may have functional implications. Chemokine receptors
were shown to respond to their appropriate chemokine ligands with
increases in intracellular calcium that, in the case of neurons,
required predepolarization with KCl. These responses were blocked by
neutralizing chemokine receptor in mAbs. Pretreatment of neural cells
with pertussis toxin abolished responses to stromal-derived
factor-1
, macrophage inflammatory protein-1
, and RANTES,
indicating coupling of CCR5 and CXCR4 to a Gi protein,
as in leukocytes. Cultured macaque neurons demonstrated calcium flux
response to treatment with recombinant SIVmac239 envelope protein,
suggesting a mechanism by which viral envelope could affect neuronal
function in SIV infection. The presence of functional chemokine
receptors on neurons and astrocytes suggests that chemokines could
serve to link inflammatory and neuronal
responses.
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