Naturally occurring deletional mutation in the C-terminal cytoplasmic tailof CCR5 affects surface trafficking of CCR5

CCR5 is an essential coreceptor for the cellular entry of R5 strains of hum an immunodeficiency virus type 1 (HIV-1). CCR5-893(-) is a single-nucleotid e deletion mutation which is observed exclusively in Asians (M. A. Ansari-L ari, et al., Nat, Genet. 16:221-222, 1997), This mutant gene produces a CCR 5 which lacks the entire C-terminal cytoplasmic tail. To assess the effect of CCR5-893(-) on HIV-1 infection, we generated a recombinant Sendai virus expressing the mutant CCR5 and compared its HIV-1 coreceptor activity with that of wild-type CCR5. Although the mutant CCR5 has intact extracellular d omains, its coreceptor activity was much less than that of wild-type CCR5. Flow cytometric analyses and confocal microscopic observation of cells expr essing the mutant CCR5 revealed that surface CCR5 levels were greatly reduc ed in these cells, while cytoplasmic CCR5 levels of the mutant CCR5 were co mparable to that of the wild type. Peripheral blood CD4(+) T cells obtained from individuals heterozygous for this allele expressed very low levels of CCR5. These data suggest that the CCR5-893(-) mutation affects intracellul ar transport of CCR5 and raise the possibility that this mutation also affe cts HIV-1 transmission and disease progression.