Polymorphism in RANTES chemokine promoter affects HIV-1 disease progression

RANTES (regulated on activation normal T cell expressed and secreted) is on e of the natural ligands for the chemokine receptor CCR5 and potently suppr esses 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 variati ons in their ability to secrete RANTES. These findings prompted us to analy ze the upstream noncoding region of the RANTES gene, which contains cis-act ing elements involved in RANTES promoter activity, in 272 HIV-l-infected an d 193 non-HIV-l-infected individuals in Japan. Our results showed that ther e were two polymorphic positions, one of which was associated with reduced CD4+ lymphocyte depletion rates during untreated periods in HIV-l-infected individuals. This mutation, RANTES-28G, occurred at an allele frequency of approximate to 17% in the non-HIV-l-infected Japanese population and exerte d no influence on the incidence of HIV-1 infection. Functional analyses of RANTES promoter activity indicated that the RANTES-28G mutation increases t ranscription of the RANTES gene. Taken together, these data suggest that th e RANTES-28G mutation increases RANTES expression in HIV-l-infected individ uals and thus delays the progression of the HIV-1 disease.