McDermott D H, Zimmerman P A, Guignard F, Kleeberger C A, Leitman S F, Murphy P M
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Lancet. 1998 Sep 12;352(9131):866-70. doi: 10.1016/s0140-6736(98)04158-0.
The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 delta32 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.
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.
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 delta32 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.
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 delta32 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.
感染HIV-1的个体发展为艾滋病的速率各不相同。相关因素包括两种遗传的人类等位基因，CCR5 Δ32和CCR2-641，它们改变了HIV-1共受体/趋化因子受体CCR５和CCR2b的蛋白质编码区域。我们检验了CCR5启动子多态性可能影响HIV-1感染者发展为艾滋病速率的假说。
我们采用定向异源双链分析来鉴定CCR5启动子中的多态性。在体外将启动子变体与氯霉素乙酰转移酶报告基因进行比较，并通过对在多态性位点不一致的HIV-1血清转化者进行基因分型来进行体内研究。
在CCR5启动子的59029碱基对处（基因库U95626）鉴定出A/G多态性。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）。在一组既缺乏CCR5 Δ32又缺乏CCR2-641的HIV-1血清转化者中，59029-G/G个体发展为艾滋病的平均速度比59029-A/A个体慢3.8年（p=0.004）。59029-G/A不一致性与不一致的感染率无关。
我们的结果与CCR5在HIV-1发病机制中起重要作用的假说一致。相对于CCR5 59029-A/A，CCR5 59029-G/G似乎具有保护作用，相对于CCR5 Δ32或CCR2-641，其保护作用约为两倍。这种效应可能是CCR5 mRNA产生减少的结果。这些结果确定了CCR5启动子中第一个可能成为治疗HIV-1感染有用靶点的位点。
