Expression of CCR5, a major coreceptor for human immunodeficiency virus type 1 (HIV-1), is regulated by a number of transcription factors. Here we report that the YY1 transcription factor down-regulates CCR5 promoter activity and that overexpression of YY1 reduces cell surface CCR5 expression and infectibility by R5-HIV-1. Because YY1 also down-regulates promoter activities of CXCR4, another major coreceptor for HIV-1 and HIV-1 long terminal repeat, this transcription factor may play a critical role in the pathogenesis of HIV-1 disease.