HOMOZYGOUS DEFECT IN HIV-1 CORECEPTOR ACCOUNTS FOR RESISTANCE OF SOMEMULTIPLY-EXPOSED INDIVIDUALS TO HIV-1 INFECTION

Rare individuals have been multiply exposed to HIV-1 but remain uninfe cted. The CD4(+) T-cells of two of these individuals, designated EU2 a nd EU3, are highly resistant in vitro to the entry of primary macropha ge-tropic virus but are readily infectable with transformed T-cell lin e adapted viruses. We report here on the genetic basis of this resista nce. We found that EU2 and EU3 have a homozygous defect in CKR-5, the gene encoding the recently described coreceptor for primary HIV-1 isol ates. These individuals appear to have inherited a defective CKR-5 all ele that contains an internal 32 base pair deletion. The encoded prote in is severely truncated and cannot be detected at the cell surface. S urprisingly, this defect has no obvious phenotype in the affected indi viduals. Thus, a CKR-5 allele present in the human population appears to protect homozygous individuals from sexual transmission of HIV-1. H eterozygous individuals are quite common (similar to 20%) in some popu lations. These findings indicate the importance of CKR-5 in HIV-1 tran smission and suggest that targeting the HIV-1-CKR-5 interaction may pr ovide a means of preventing or slowing disease progression.