Identification of certain chemokine receptors as fusion/entry co-factors for HIV and the recognition that their ligands function as HIV suppressive factors has substantially extended our understanding of HIV pathogenesis. CCR5, a receptor for the beta chemokines RANTES, MIP-1-alpha, and MIP-1-beta, serves as a co-receptor for macrophage (M)-tropic HIV, while CXCR4, a receptor for the alpha chemokine SDF-1, is critical for fusion/entry of T cell (T)-tropic HIV. Recently, an orphan receptor, STRL33 has been shown to serve as a fusion/entry cofactor for various HIV and simian immunodeficiency virus strains. Recent findings that a genetic defect in the CCR5 gene confers resistance to HIV infection has confirmed its significance in HIV pathogenesis. However, in addition to genetic factors affecting expression of these proteins, immunoregulatory mechanisms which can affect the availability of functional co-receptors may influence transmission of either phenotype of HIV, transition from a predominance of one phenotype over the other, and the prognosis of HIV disease. In order to investigate the molecular and cellular mechanisms that control expression of HIV co-receptors and their ligands, we cloned and characterized the promoter regions for the genes encoding these proteins, namely RANTES, CCR5, CXCR4, and STRL33. We have identified cis-acting elements involved in regulation of those promoters, and determined molecular mechanisms whereby those promoters are regulated. (A) Regulation of CCR5 promoter We have demonstrated that several transcriptional factors such as Oct2 and GATA1 can transactivate CCR5 promoter through those elements. We have also demonstrated that retinoic acid, which can induce CCR5 expression in promonocytic cell lines, is able to upregulate CCR5 promoter activity, and that lipopolysaccharide, a bacterial product, downregulates CCR5 promoter activity in macrophages. (B) Regulation of CXCR4 promoter We have demonstrated that the transcriptional factors NRF1, c-Myc, USF1, and USF2 upregulate, while YY1 downregulates CXCR4 promoter activity through those elements. (C) Regulation of STRL33 promoter We have cloned and characterized the STRL33 promoter region, and identified several cis-acting elements on the promoter. We have demonstrated that stimulation with either phorbol myristate acetate/ionomycin, lipopolysaccharide or prostaglandin E2 upregulates STRL33 promoter activity.
