A putative G protein-coupled receptor, RDC1, is a novel coreceptor for human and simian immunodeficiency viruses

More than 10 G protein-coupled receptors (GPCRs) have been shown to act as coreceptors for infection of human immunodeficiency virus type 1 (HIV-1), H IV-2, and simian immunodeficiency virus (SIV). We have isolated HIV-1 varia nts infectious to primary brain-derived CD4-positive cells (BT-3 and BT-20/ N) and U87/CD4 glioma cells that are resistant to T-cell line-tropic (T-tro pic), macrophage-tropic (M-tropic), and T- and M-tropic (dualtropic) (X4, R 5, and R5X4) HIV-I strains. These primary brain-derived cells were also hig hly susceptible to HIV-2(ROD), HIV-2(SBL6669), and SIVmndGB-1. A factor or coreceptor that determines the susceptibility of these brain-derived cells to these HIV and SIV strains has not been fully identified. To identify thi s coreceptor, we examined amino acid sequences of all known HIV and SIV cor eceptors and noticed that tyrosine residues are well conserved in their ext racellular amino-terminal domains. By this criterion, we selected 18 GPCRs as candidates of coreceptors for HIV and SIV strains infectious to these br ain-derived cells. mRNA expression of an orphan GPCR, RDC1, was detected in the brain-derived cells, the C8166 T-cell line, and peripheral blood lymph ocytes, all of which are susceptible to HIV-1 variants, but not in macropha ges, which are resistant to them. When a CD4-expressing cell line, NP-2/CD4 , which shows strict resistance to infection not only with HIV-1 but also w ith HIV-2 or SIV, was transduced with the RDC1 gene, the cells became highl y susceptible to HIV-2 and SIVmnd strains but to neither M- nor T-tropic HI V-1 strains. The cells also acquired a low susceptibility to the HIV-1 vari ants. These findings indicate that RDC1 is a novel coreceptor for several H IV-1, HIV-2, and SIV strains which infect brain-derived cells.