A. VasilescuY. TerashimaM. EnomotoS. HeathV. PoonpiriyaH. GatanagaH. DoG. DiopT. HirtzigP. AuewarakulD. LauhakirtiT. SuraP. CharneauS. MarulloA. TherwathS. OkaS. KanegasakiM. LathropK. MatsushimaJ. F. ZaguryF. MatsudaCentre National de GenotypageInsermUniversity of TokyoEffector Cell Institute, Inc.National Center for Global Health and MedicineMahidol UniversityInstitut Pasteur, ParisInstitut CochinUniversite Paris 7- Denis DiderotKyoto UniversityArts et Metiers ParisTech2018-08-242018-08-242007-02-27Proceedings of the National Academy of Sciences of the United States of America. Vol.104, No.9 (2007), 3354-3359002784242-s2.0-33847649978https://repository.li.mahidol.ac.th/handle/20.500.14594/25165Chemokines 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-Na) 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-1NL4-3infection 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. © 2007 by The National Academy of Sciences of the USA.Mahidol UniversityMultidisciplinaryArticleSCOPUS10.1073/pnas.0611670104