Combined Effect of CCR5-Δ32 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) ⌬32, 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 ⌬32 allele (P ‫؍‬ 0.012). No protective influence of the CCR2-64I allele was observed. The haplotypes CCR5 ORF ⌬32/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 ⌬32/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.

Reduction of CCR5 with low-dose rapamycin enhances the antiviral activity of vicriviroc against both sensitive and drug-resistant HIV-1

“…In contrast, measured CD4 density values were similar among the donors (range of 22.4-27.0 ϫ 10 3 CD4 receptors/cell) (data not shown). These density values for CCR5 and CD4 are within the ranges reported by others (9)(10)(11)(12). Interestingly, VCV EC 50 values varied ϳ 20-fold among the different donors and correlated positively with CCR5 densities (Spearman's correlation test; r ϭ 0.746, P ϭ 0.0034).…”

“…We first evaluated the effect of CCR5 levels on the antiviral activity of VCV using cell lines JC10 (ϳ 2 ϫ 10 3 CCR5/cell) and JC57 (ϳ 9 ϫ 10 3 CCR5/cell), which express CD4 levels similar to those in normal CD4 T cells and whose CCR5 densities correspond to the approximate lower and upper levels of CCR5 expression in donors (9)(10)(11)(12). We infected each clone with the R5 HIV-1 strains JRFL and CC1/85 (multiplicity of infection, MOI ϭ 0.01) in the presence of varying concentrations of VCV (0.03-30 nM) for 3 h. For comparison, cells also were infected in the presence of the reverse transcriptase inhibitor efavirenz (0.003-3 nM).…”

“…Coreceptor CCR5 antagonists inhibit CCR5-tropic HIV-1 (referred to as ''R5 HIV-1'') strains, which are responsible for most transmissions and generally are present throughout the course of infection. In normal individuals, CCR5 density (receptors/cell) on CD4 lymphocytes ranges between ϳ 2 ϫ 10 3 and ϳ 10 ϫ 10 3 (9)(10)(11)(12), and this variation influences disease progression and response to therapy in HIV-1 infection (11,13).…”

CCR5Δ3259537-G/A Promoter Polymorphism Is Associated with Low Translational Efficiency and the Loss ofCCR5Δ32Protective Effects

“…Previous studies suggested that a 59029-G/A polymorphism in the CCR5 promoter was associated with a differential regulation of CCR5 transcription (26). Other studies demonstrated that some individuals who practice high-risk sexual behavior may resist infection because they posses one CCR5⌬32 allele plus a 59029-A/G genotype combination, which is apparently associated with relatively weak CCR5 expression (18). This newfound complexity in the vagaries of CCR5⌬32 expression and function might increase the clarity of the genomic analysis of risk factors for HIV infection and disease progression.…”

Global human genetics of HIV-1 infection and China

“…However, our recent study suggests that individuals with the combination of heterozygous CCR5-32 and P1 CCR5 promoter genotype (see below) are relatively resistant to HIV-1 transmission [74]. According to most reports [47-49, 55, 75-81] but not all [82,83], individuals with heterozygous CCR5-32 progress from HIV-1 infection to AIDS more slowly than persons with two normal CCR5 alleles.…”