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Polymorphism in RANTES Chemokine Promoter Affects HIV-1 Disease Progression in Japanese and Distributes Differently in Asians, Africans, and Caucasians H. LIU*1, D. CHAO1, E. E. NAKAYAMA1, H. TAGUCHI1, M. GOTO1, X. XIN1, Y. TAKEBE2, C. WASI3, J. MA4, W. LIANG4, I. THEODOROU5, M. MAGIEROWSKA5, R. KRISHNAMOORTY6, A. CHAVENTRE7, French ALT , IMMUNOCO Study Groups, P. DEBRE5, T. NAKAMURA1, Y. NAGAI1, A. IWAMOTO1, and T. SHIODA. 1Inst. Med. Sci., Univ. of Tokyo; 2Natl. Inst. of Infectious Diseases, Tokyo, Japan; 3Mahidol Univ., Bangkok, Thailand; 4Shandong Blood Ctr., Jinan, China; 5Hosp. Pitie-Salpetriere, Paris, France; 6Hosp. Robert Debre, Paris, France; and 7Univ. Victor Segalen, Bordeaux, France RANTES is one of the ligands of CCR5 and potently suppresses R5 strains of HIV-1. Previous studies demonstrated that CD4+ lymphocytes obtained from different individuals showed wide variations in their ability to secrete RANTES. These findings prompted us to analyze the immediate upstream non-coding region of RANTES gene in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were three distinct RANTES haplotypes, one of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HlV-1-infected individuals (6.86 vs 3.04 cells/ml/month, P=0.008). This haplotype, haplotype III, occurred at an allele frequency of 16.6% among non-HIV-1-infected Japanese, and exerted no influence on the incidence of HIV-1 infection. The frequencies of other haplotypes, I and II, in non-HIV-1-infected subjects were 62.4% and 21.0% respectively. Haplotype III was also associated with an elevated promoter activity. Taken together, these data suggested that the mutations in haplotype III increase the RANTES expression in HIV-1-infected individuals and thus delay HIV-1 disease progression. Analyses of RANTES promoters in other ethnic groups revealed that the frequencies of haplotype III were 13.3%, 7.0%, and 3.0% in 30 Chinese, 112 Thailanders, and 185 Caucasians, respectively. Strikingly, haplotype III was completely absent and haplotype II was more abundant (62%) in 54 African subjects. These data suggested that the mutation specific for haplotype III occurred after the separation of Caucasians and Asians from Africans and that the most ancestral haplotype is haplotype II. The restricted prevalence of haplotype III in Asians might indicate that a region-specific selective pressure operated to elevate its frequency. Key Words: disease progression, polymorphism, RANTES |
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© 7th
Conference on Retroviruses and Opportunistic Infections, |