title: Combined effect of CCR5-Delta32 heterozygosity and the CCR5 promoter polymorphism -2459 A/G on CCR5 expression and resistance to human immunodeficiency virus type 1 transmission.
abstract: Exposed seronegative individuals (ES) with persistent high-risk sexual behavior may be less susceptible to human immunodeficiency virus type 1 (HIV-1) infection because they carry the chemokine receptor (CR) gene alleles CCR5 open reading frame (ORF) Delta32, CCR5 promoter -2459G, or CCR2 ORF 64I (CCR2-64I), all of which have been found to diminish HIV-1 infectivity and/or disease progression. To investigate this, we determined the haplotypes for these three genetic loci in 93 ES and 247 low-risk control individuals. To test if protective haplotypes exert their effect by modulating CR expression, we measured the protein expression of CCR5 and CXCR4 on circulating CD4+ T cells and CD14+ monocytes in 71 ES and 92 controls. To avoid investigator bias, the analysis was performed without knowledge of each subject's risk and genotype. The CCR5 -2459G allele was significantly enriched in ES Caucasian men, who constituted the majority (84%) of the ES cohort, compared to the control Caucasian men (P = 0.02). This increase was mostly attributable to a higher frequency of the -2459 A/G versus the -2459 A/A genotype in individuals heterozygous for the delta32 allele (P = 0.012). No protective influence of the CCR2-64I allele was observed. The haplotypes CCR5 ORF delta32/CCR5 -2459A (in complete linkage disequilibrium) and CCR5 ORF wt/CCR5 -2459G had a cumulative negative effect on the expression of CCR5, since we measured significantly reduced CCR5 densities on both T-helper cells and monocytes only when both haplotypes were present. Densities of CCR5 on lymphocytes and monocytes were correlated (r = 0.59; P < 0.0001), indicating concordance of CCR5 expression patterns across different cell types. We conclude that the CCR5 ORF delta32/wt-CCR5 -2459 A/G genotype combination offers an advantage in resisting sexual HIV-1 transmission and that this effect is mediated by a relative paucity of CCR5 on potential target cells of HIV-1.
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, Program in Infectious Diseases, 1100 Fairview Ave. N., P.O. Box 19024, D3-100, Seattle, WA 98109-1024, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Hladik
authors.forename: Huanliang
authors.initials: H
authors.lastname: Liu
authors.forename: Emily
authors.initials: E
authors.lastname: Speelmon
authors.forename: Devon
authors.initials: D
authors.lastname: Livingston-Rosanoff
authors.forename: Sean
authors.initials: S
authors.lastname: Wilson
authors.forename: Polachai
authors.initials: P
authors.lastname: Sakchalathorn
authors.forename: Yon
authors.initials: Y
authors.lastname: Hwangbo
authors.forename: Benjamin
authors.initials: B
authors.lastname: Greene
authors.forename: Tuofu
authors.initials: T
authors.lastname: Zhu
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000635:transmission; D018023:HIV Seronegativity / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000472:pathogenicity; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009000:Monocytes / Q000276:immunology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D019713:Receptors, CCR5 / Q000235:genetics*; D012309:Risk-Taking
chemical_list: D019713:Receptors, CCR5; D004247:DNA