HIV-1-resistance phenotype conferred by combination of two separate inherited mutations of CCR5 gene

Lancet
C QuillentA Beretta

Abstract

Despite multiple exposures to HIV-1, some individuals remain uninfected, and their peripheral-blood mononuclear cells (PBMC) are resistant to in-vitro infection by primary HIV-1 isolates. Such resistance has been associated with a homozygous 32-base-pair deletion (delta 32) in the C-C chemokine receptor gene CCR5. We examined other mutations of the CCR5 gene that could be associated with resistance to HIV-1 infection. 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 ...Continue Reading

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