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
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
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DOI：
10.1128/jvi.79.18.11677-11684.2005
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发表时间：
2005-09-01
影响因子：
5.4
通讯作者：
McElrath, MJ
中科院分区：
文献类型：
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作者：
Hladik, F;Liu, HL;McElrath, MJ
具有持续高风险性行为的暴露血清阴性个体（ES）可能对人类免疫缺陷病毒1型（HIV-1）感染较不敏感，因为他们携带趋化因子受体（CR）基因等位基因CCR 5开放阅读框（ORF）Delta 32、CCR 5启动子-2459 G或CCR 2 ORF 641（CCR 2 -641），所有这些都被发现减少HIV-1感染性和/或疾病进展。为了调查这一点，我们确定了这三个遗传位点的单倍型在93 ES和247个低风险的控制个人。为了测试保护性单倍型是否通过调节CR表达发挥其作用，我们测量了71例ES和92例对照组循环CD 4（+）T细胞和CD 14（+）单核细胞上CCR 5和CXCR 4的蛋白表达。为了避免研究者偏倚，在不了解每个受试者的风险和基因型的情况下进行分析。与对照高加索男性相比，CCR 5 - 2459 G等位基因在ES高加索男性中显著富集，其构成了ES队列的大多数（84%）（P = 0.02）。这种增加主要归因于A32等位基因杂合子个体中-2459 A/G基因型频率高于-2459 A/A基因型（P = 0.012）。未观察到CCR 2 -641等位基因的保护作用。单倍型CCR 5 ORF Delta 32/CCR 5 - 2459 A（处于完全连锁不平衡）和CCR 5 ORF wt/CCR 5 - 2459 G对CCR 5的表达具有累积的负面影响，因为我们仅在两种单倍型都存在时才测量到T辅助细胞和单核细胞上CCR 5密度的显著降低。淋巴细胞和单核细胞上的CCR 5密度相关（r = 0.59; P < 0.0001），表明不同细胞类型的CCR 5表达模式一致。我们得出结论，CCR 5 ORF Delta 32/wt-CCR 5 - 2459 A/G基因型组合在抵抗HIV-1性传播方面具有优势，并且这种作用是由HIV-1潜在靶细胞上相对缺乏的CCR 5介导的。
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) Delta 32, CCR5 promoter -2459G, or CCR2 ORF 641 (CCR2-641), 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 A32 allele (P = 0.012). No protective influence of the CCR2-641 allele was observed. The haplotypes CCR5 ORF Delta 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 Delta 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.