HIV-1-RESISTANCE PHENOTYPE CONFERRED BY COMBINATION OF 2 SEPARATE INHERITED MUTATIONS OF CCR5 GENE

Background Despite multiple exposures to HIV-1, some individuals remai n uninfected, and their peripheral-blood mononuclear cells (PBMC) are resistant to in-vitro infection by primary HIV-1 isolates. Such resist ance has been associated with a homozygous 32-base-pair deletion (Delt a 32) in the C-C chemokine receptor gene CCR5. We examined other mutat ions of the CCR5 gene that could be associated with resistance to HIV- 1 infection. Methods We assessed the susceptibility of PBMC to in-vitr o infection by HIV-1 isolates that use the CCR5 as the major corecepto r for Viral entry in 18 men who had frequent unprotected sexual interc ourse with a seropositive partner. We also did genotypic analysis of C CR5 alleles. One of the 18 exposed bur uninfected men (who we refer to as ExU2) showed total resistance to in-vitro infection by CCR5-depend ent viruses, and was found to carry a CCR5 Delta 32 allele and a singl e 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 exist ed in the general population, we did genetic analyses of the CCR5 geno type in ExU2's father and sister and also in 209 healthy blood donors who were not exposed to HIV-1. Findings The m303 mutation found in ExU 2 introduced a premature stop codon and prevented the expression of a functional coreceptor. The family studies revealed that the m303 mutan t allele was inherited as a single mendelian trait. Genotype analysis showed that three of the 209 healthy blood donors were heterozygous fo r the mutant allele. Interpretation We characterise a new CCR5 gene mu tation, present in the general population, that prevents expression of functional coreceptors from the abnormal allele and confers resistanc e to HIV-1 infection when associated to the Delta 32 CCR5 mutant gene.