Vasilescu A, Terashima Y, Enomoto M, Heath S, Poonpiriya V, Gatanaga H, Do H, Diop G, Hirtzig T, Auewarakul P, Lauhakirti D, Sura T, Charneau P, Marullo S, Therwath A, Oka S, Kanegasaki S, Lathrop M, Matsushima K, Zagury J-F, Matsuda F
Centre National de Génotypage, 91057 Evry, France.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3354-9. doi: 10.1073/pnas.0611670104. Epub 2007 Feb 21.
Chemokines and their receptors are key factors in the onset and progression of AIDS. Among them, accumulating evidence strongly indicates the involvement of IL-8 and its receptors, CXCR1 and CXCR2, in AIDS-related conditions. Through extensive investigation of genetic variations of the human CXCR1-CXCR2 locus, we identified a haplotype of the CXCR1 gene (CXCR1-Ha) carrying two nonsynonymous single nucleotide polymorphisms, CXCR1_300 (Met to Arg) in the N terminus extracellular domain and CXCR1_142 (Arg to Cys) in the C terminus intracellular domain. Transfection experiments with CXCR1 cDNAs corresponding to the CXCR1-Ha and the alternative CXCR1-HA haplotype showed reduced expression of CD4 and CXCR4 in CXCR1-Ha cells in human osteosarcoma cells as well as in Jurkat and CEM human T lymphocytes. Furthermore, the efficiency of X4-tropic HIV-1(NL4-3) infection was significantly lower in CXCR1-Ha cells than in CXCR1-HA cells. The results were further confirmed by a series of experiments using six HIV-1 clinical isolates from AIDS patients. A genetic association study was performed by using an HIV-1(+) patient cohort consisting of two subpopulations of AIDS with extreme phenotypes of rapid and slow progression of the disease. The frequency of the CXCR1-Ha allele is markedly less frequent in patients with rapid disease onset than those with slow progression (P = 0.0003). These results provide strong evidence of a protective role of the CXCR1-Ha allele on disease progression in AIDS, probably acting through modulation of CD4 and CXCR4 expression.
趋化因子及其受体是艾滋病发病和进展的关键因素。其中，越来越多的证据有力地表明白细胞介素-8及其受体CXCR1和CXCR2参与了与艾滋病相关的病症。通过对人类CXCR1 - CXCR2基因座的遗传变异进行广泛研究，我们鉴定出一种CXCR1基因的单倍型（CXCR1-Ha），其携带两个非同义单核苷酸多态性，即位于N端细胞外结构域的CXCR1_300（甲硫氨酸变为精氨酸）和位于C端细胞内结构域的CXCR1_142（精氨酸变为半胱氨酸）。用与CXCR1-Ha及另一种CXCR1-HA单倍型相对应的CXCR1 cDNA进行转染实验，结果显示在人骨肉瘤细胞以及Jurkat和CEM人T淋巴细胞中，CXCR1-Ha细胞中CD4和CXCR4的表达降低。此外，X4嗜性HIV-1（NL4-3）在CXCR1-Ha细胞中的感染效率明显低于CXCR1-HA细胞。使用来自艾滋病患者的六种HIV-1临床分离株进行的一系列实验进一步证实了这些结果。通过使用一个HIV-1阳性患者队列进行遗传关联研究，该队列由两个具有疾病快速和缓慢进展极端表型的艾滋病亚群组成。疾病快速发作的患者中CXCR1-Ha等位基因的频率明显低于疾病进展缓慢的患者（P = 0.0003）。这些结果提供了强有力的证据，表明CXCR1-Ha等位基因对艾滋病疾病进展具有保护作用，可能是通过调节CD4和CXCR4的表达来实现的。
