Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene
Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene
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DOI：
10.1038/382722a0
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发表时间：
1996-08-22
期刊：
影响因子：
64.8
通讯作者：
Parmentier, M
中科院分区：
文献类型：
--
作者：
Samson, M;Libert, F;Parmentier, M
HIV-1和相关病毒除了CD 4外还需要共受体来感染靶细胞。最近证明趋化因子受体CCR-5（参考文献1）是嗜巨噬细胞（M-嗜性）HIV-1毒株的共受体（2-6），孤儿（7）受体LESTR（也称为融合蛋白）允许适应在转化T细胞系中生长的毒株（T-嗜性毒株）感染。在这里，我们表明，CCR-5的突变等位基因是目前在高加索人群中的高频率（等位基因频率，0.092），但不存在于非洲西部和中部的黑人人口和日本人口。编码区内的32个碱基对缺失导致移码，并产生不支持巨噬细胞和双嗜性HIV-1毒株的膜融合或感染的非功能性受体。在一组HIV-1感染的白人受试者中，没有发现突变的纯合子个体，杂合子的频率比一般人群低35%。发现来自无效等位基因纯合个体的白色血细胞对M嗜性HIV-1病毒感染具有高度抗性，证实CCR-5是主要HIV-1毒株的主要α受体。血清阳性患者中杂合子频率较低可能表明部分抗性。
HIV-1 and related viruses require co-receptors, in addition to CD4, to infect target cells. The chemokine receptor CCR-5 (ref. 1) was recently demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1 strains(2-6), and the orphan(7) receptor LESTR (also called fusin) allows infection by strains adapted for growth in transformed T-cell lines (T-tropic strains). Here we show that a mutant allele of CCR-5 is present at a high frequency in caucasian populations (allele frequency, 0.092), but is absent in 'black populations from Western and Central Africa and Japanese populations. A 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains. In a cohort of HIV-1-infected caucasian subjects, no individual homozygous for the mutation was found, and the frequency of heterozygotes was 35% lower than in the general population. White blood cells from an individual homozygous for the null allele were found to be highly resistant to infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major cc-receptor for primary HIV-1 strains, The lower frequency of heterozygotes in seropositive patients may indicate partial resistance.