Production of Specific mRNA Transcripts, Usage of an Alternate Promoter, and Octamer-Binding Transcription Factors Influence the Surface Expression Levels of the HIV Coreceptor CCR5 on Primary T Cells

• Published in: Journal of Immunology 2007-05, Vol.178 (9), p.5668-5681
• Main Authors: Mummidi, Srinivas, Adams, Lisa M, VanCompernolle, Scott E, Kalkonde, Mrunal, Camargo, Jose F, Kulkarni, Hemant, Bellinger, Adam S, Bonello, Gregory, Tagoh, Hiromi, Ahuja, Seema S, Unutmaz, Derya, Ahuja, Sunil K
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; CD4-Positive T-Lymphocytes - immunology; Cell Membrane - chemistry; Cell Membrane - metabolism; Cells, Cultured; Exons; Gene Expression Regulation; HIV-1 - immunology; Human immunodeficiency virus 1; Humans; Molecular Sequence Data; Octamer Transcription Factor-1 - genetics; Octamer Transcription Factor-1 - metabolism; Octamer Transcription Factor-2 - genetics; Octamer Transcription Factor-2 - metabolism; Promoter Regions, Genetic - genetics; Receptors, CCR5 - analysis; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; RNA, Messenger - metabolism; Transcription, Genetic
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.178.9.5668

Surface levels of CCR5 on memory CD4(+) T cells influence HIV-1/AIDS susceptibility. Alternative promoter usage results in the generation of CCR5 mRNA isoforms that differ based on whether they contain or lack the untranslated exon 1. The impact of exon 1-containing transcripts on CCR5 surface expression is unknown. In this study, we show that the increased cell surface expression of CCR5 on primary T cells is associated with selective enrichment of exon 1-containing transcripts. The promoter that drives exon 1-containing transcripts is highly active in primary human T cells but not in transformed T cell lines. The transcription factors Oct-1 and -2 inhibit and enhance, respectively, the expression of exon 1-containing transcripts and CCR5 surface levels. However, polymorphisms at homologous octamer-binding sites in the CCR5 promoter of nonhuman primates abrogate the binding of these transcription factors. These results identify exon 1-containing transcripts, and the cis-trans factors that regulate the expression levels of these mRNA isoforms as key parameters that affect CCR5 surface expression levels, and by extension, susceptibility to HIV/AIDS among humans, and possibly, the observed interspecies differences in susceptibility to lentiviral infection.