Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates

Microglia are the main human immunodeficiency virus (HIV) reservoir in the central nervous system and most likely play a major role in the development of HIV dementia (HIVD). To characterize human adult microglial chemokine r eceptors, we analyzed the expression and calcium signaling of CCR5, CCR3, a nd CXCR4 and their roles in HIV entry. Microglia expressed higher levels of CCR5 than of either CCR3 or CXCR4. Of these three chemokine receptors, onl y CCR5 and CXCR4 were able to transduce a signal in microglia in response t o their respective ligands, MIP-1 beta and SDF-1 alpha, as recorded by sing le-cell calcium flux experiments. We also found that CCR5 is the predominan t coreceptor used for infection of human adult microglia by the HIV type 1 dementia isolates HIV-1(DS-br), HIV-1(RC-br), and HIV-1(YU-2), since the an ti-CCR5 antibody 2D7 was able to dramatically inhibit microglial infection by both wild-type and single-round luciferase pseudotype reporter viruses. Anti-CCR3 (7B11) and anti-CXCR4 (12G5) antibodies had little or no effect o n infection. Last, we found that virus pseudotyped with the DS-br and RC-br envelopes can infect cells transfected with CD4 in conjunction with the G- protein-coupled receptors APJ, CCR8, and GPR15, which have been previously implicated in HIV entry.