CCR5 promoter polymorphism and HIV-1 disease progression
CCR5 promoter polymorphism and HIV-1 disease progression
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DOI：
10.1016/s0140-6736(98)04158-0
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发表时间：
1998-09-12
期刊：
影响因子：
168.9
通讯作者：
Murphy, PM
中科院分区：
文献类型：
--
作者：
McDermott, DH;Zimmerman, PA;Murphy, PM
背景HIV-1感染者进展为艾滋病的速度各不相同。相关因素包括两个遗传的人类等位基因，CCR 5 Delta 32和CCR 2 -641，它们改变了HIV-1辅助受体/趋化因子受体CCR 5和CCR 2b的蛋白编码区。我们测试的假设，CCR 5启动子的多态性可能会影响HIV-1感染者的进展到AIDS的速度。方法我们使用定向异源双链分析，以确定CCR 5启动子的多态性。启动子的变体进行了比较，在体外与氯霉素乙酰转移酶报告基因，并在体内通过基因分型HIV-1血清转化者不一致的多态性位点，结果A/G多态性被确定在碱基对59029（Genbank U95626）在CCR 5启动子。两种启动子等位基因都很常见（59029-A的等位基因频率为43-68%，取决于种族）。当测量体外启动子活性时，59029-G的活性比59029-A低45%（p=0.05）。在缺乏CCR 5 Delta 32和CCR 2 -641的HIV-1血清转化者队列中，59029-G/G个体进展为AIDS比59029-A/A个体平均慢3.8年（p=0.004）。59029-G/A的不一致性与不一致的感染率无关。解释我们的结果与CCR 5在HIV-1发病机制中很重要的假设一致，CCR 5 59029-G/G似乎相对于CCR 5 59029-A/A具有保护性，并且相对于CCR 5 Delta 32或CCR 2 -641具有大约两倍的保护性。这种效应可能是减少CCR 5 mRNA产生的结果。这些结果确定了CCR 5启动子中的第一个位点，该位点可能是治疗HIV-1感染的有用靶点。
Background The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 Delta 32 and CCR2-641, which alter the protein-coding regions for the HIV-1 coreceptors/chemokine receptors CCR5 and CCR2b. We tested the hypothesis that polymorphisms of the CCR5 promoter might affect the rate of progression of HIV-1 infected people to AIDS.Methods We used directed heteroduplex analysis to identify polymorphism in the CCR5 promoter. Promoter-variants were compared in vitro with a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping HIV-1 seroconvertors discordant at polymorphous loci,Findings An A/G polymorphism was identified at basepair 59029 (Genbank U95626) in the CCR5 promoter. Both promoter alleles were common (43-68% allelic frequency for 59029-A depending on race). When in-vitro promoter activity was measured, 59029-G had 45% lower activity than 59029-A (p=0.05). In a cohort of HIV-1 seroconvertors lacking both CCR5 Delta 32 and CCR2-641, 59029-G/G individuals progressed to AIDS on average 3.8 years more slowly than 59029-A/A individuals (p=0.004). 59029-G/A discordance did not correlate with discordant rates of infection.Interpretation Our results are consistent with the hypothesis that CCR5 is important in HIV-1 pathogenesis, CCR5 59029-G/G appears to be protective relative to CCR5 59029-A/A, and about twice as protective relative to CCR5 Delta 32 or CCR2-641. This effect may be the result of reduced CCR5 mRNA production. These results identify the first site in the CCR5 promoter that may be a useful target for treatment of HIV-1 infection.