A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1+ patients.
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.
Vasilescu
A
A
Centre National de Génotypage, 91057 Evry, France.
Terashima
Y
Y
Enomoto
M
M
Heath
S
S
Poonpiriya
V
V
Gatanaga
H
H
Do
H
H
Diop
G
G
Hirtzig
T
T
Auewarakul
P
P
Lauhakirti
D
D
Sura
T
T
Charneau
P
P
Marullo
S
S
Therwath
A
A
Oka
S
S
Kanegasaki
S
S
Lathrop
M
M
Matsushima
K
K
Zagury
J-F
JF
Matsuda
F
F
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*
D015704:CD4 Antigens; D019718:Receptors, CXCR4; D023062:Receptors, Interleukin-8A