We assessed the susceptibility of PBMC to in-vitro infection by HIV-1 isolates that use the CCR5 as the major coreceptor for viral entry in 18 men who had frequent unprotected sexual intercourse with a seropositive partner. We also did genotypic analysis of CCR5 alleles. One of the 18 exposed but uninfected men (who we refer to as ExU2) showed total resistance to in-vitro infection by CCR5-dependent viruses, and was found to carry a CCR5 delta 32 allele and a single point mutation (T—>A) at position 303 on the other allele. To find out whether the CCR5 mutation was restricted to ExU2’s family or existed in the general population, we did genetic analyses of the CCR5 genotype in ExU2’s father and sister and also in 209 healthy blood donors who were not exposed to HIV-1.
The m303 mutation found in ExU2 introduced a premature stop codon and prevented the expression of a functional coreceptor. The family studies revealed that the m303 mutant allele was inherited as a single mendelian trait. Genotype analysis showed that three of the 209 healthy blood donors were heterozygous for the mutant allele.