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Title: A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1<sup>+</sup>patients
Authors: A. Vasilescu
Y. Terashima
M. Enomoto
S. Heath
V. Poonpiriya
H. Gatanaga
H. Do
G. Diop
T. Hirtzig
P. Auewarakul
D. Lauhakirti
T. Sura
P. Charneau
S. Marullo
A. Therwath
S. Oka
S. Kanegasaki
M. Lathrop
K. Matsushima
J. F. Zagury
F. Matsuda
Centre National de Genotypage
University of Tokyo
Effector Cell Institute, Inc.
National Center for Global Health and Medicine
Mahidol University
Institut Pasteur, Paris
Institut Cochin
Universite Paris 7- Denis Diderot
Kyoto University
Arts et Metiers ParisTech
Keywords: Multidisciplinary
Issue Date: 27-Feb-2007
Citation: Proceedings of the National Academy of Sciences of the United States of America. Vol.104, No.9 (2007), 3354-3359
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-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.
ISSN: 00278424
Appears in Collections:Scopus 2006-2010

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