title: A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients.
abstract: 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.
authors.affiliation: Centre National de Génotypage, 91057 Evry, France.
authors.forename: A
authors.initials: A
authors.lastname: Vasilescu
authors.forename: Y
authors.initials: Y
authors.lastname: Terashima
authors.forename: M
authors.initials: M
authors.lastname: Enomoto
authors.forename: S
authors.initials: S
authors.lastname: Heath
authors.forename: V
authors.initials: V
authors.lastname: Poonpiriya
authors.forename: H
authors.initials: H
authors.lastname: Gatanaga
authors.forename: H
authors.initials: H
authors.lastname: Do
authors.forename: G
authors.initials: G
authors.lastname: Diop
authors.forename: T
authors.initials: T
authors.lastname: Hirtzig
authors.forename: P
authors.initials: P
authors.lastname: Auewarakul
authors.forename: D
authors.initials: D
authors.lastname: Lauhakirti
authors.forename: T
authors.initials: T
authors.lastname: Sura
authors.forename: P
authors.initials: P
authors.lastname: Charneau
authors.forename: S
authors.initials: S
authors.lastname: Marullo
authors.forename: A
authors.initials: A
authors.lastname: Therwath
authors.forename: S
authors.initials: S
authors.lastname: Oka
authors.forename: S
authors.initials: S
authors.lastname: Kanegasaki
authors.forename: M
authors.initials: M
authors.lastname: Lathrop
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
authors.forename: J-F
authors.initials: JF
authors.lastname: Zagury
authors.forename: F
authors.initials: F
authors.lastname: Matsuda
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics*; D015153:Blotting, Western; D015704:CD4 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005434:Flow Cytometry; D040461:Gene Components; D005786:Gene Expression Regulation / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D015497:HIV-1; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019718:Receptors, CXCR4 / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000235:genetics*
chemical_list: D015704:CD4 Antigens; D019718:Receptors, CXCR4; D023062:Receptors, Interleukin-8A