A haplotype of the human CXCR1 gene protective against rapid disease progression in HIV-1⁺patients

• Main 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
• Other Authors: Centre National de Genotypage
• Format: Article
• Published: 2018
• Subjects: Multidisciplinary
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/25165
• Institution: Mahidol University

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.