RANTES (regulated on activation normal T cell expressed and secreted) is one of the natural ligands for the chemokine receptor CCR5 and potently suppresses in vitro replication of the R5 strains of HIV-1, which use CCR5 as a coreceptor. Previous studies showed that peripheral blood mononuclear cells or CD4 ؉ lymphocytes obtained from different individuals had wide variations in their ability to secrete RANTES. These findings prompted us to analyze the upstream noncoding region of the RANTES gene, which contains cis-acting elements involved in RANTES promoter activity, in 272 HIV-1-infected and 193 non-HIV-1-infected individuals in Japan. Our results showed that there were two polymorphic positions, one of which was associated with reduced CD4 ؉ lymphocyte depletion rates during untreated periods in HIV-1-infected individuals. This mutation, RANTES؊28G, occurred at an allele frequency of Ϸ17% in the non-HIV-1-infected Japanese population and exerted no inf luence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES؊28G mutation increases transcription of the RAN-TES gene. Taken together, these data suggest that the RANTES؊28G mutation increases RANTES expression in HIV-1-infected individuals and thus delays the progression of the HIV-1 disease.The chemokine receptor CCR5 is an essential coreceptor for the cellular entry of R5 strains (macrophage tropic͞non-syncytium-inducing strains) of HIV-1 (1-6), which predominate in the early stages of infection (7). During the course of infection, variants called X4 strains (T cell-line tropic͞ syncytium-inducing strains) emerge (1, 8-11), which use CXCR4 as a coreceptor (12). In vitro replication of R5 strains can be blocked by the ligands for CCR5, macrophage inflammatory peptide-1␣ and -1␤, and RANTES (regulated on activation normal T cell expressed and secreted; refs. 13 and 14), whereas that of X4 strains can be blocked by the CXCR4 ligands stromal cell derived factor-1␣ and -1␤ (15, 16).Mutations in HIV-1 coreceptors and their natural ligand genes have been shown to modify HIV-1 transmission and disease progression. Individuals homozygous for a 32-nt deletion in the CCR5 coding region were resistant to HIV-1 infection (17, 18), whereas heterozygosity delays disease progression (19,20). A single V-to-I substitution in the first transmembrane segment of CCR2, a minor coreceptor for dual tropic R5X4 strains (3, 5), has a significant impact on disease progression but not on HIV-1 transmission in cohorts of seroconverters (21,22). Finally, homozygosity of a single G-to-A mutation in the 3Ј noncoding region of the stromal cell derived factor-1␤ gene also showed a disease-retarding effect (23), although later studies could not confirm this effect (24,25).Among three natural CCR5 ligands, RANTES showed the highest potency to suppress in vitro replication of R5 strains of HIV-1 (13). Phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) or CD4 ϩ enriched lymphocytes obtained from different...

No abstract