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* Veterans Administration Center for AIDS and HIV Infection, South Texas Veterans Healthcare System and Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229;
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232;
Molecular Medicine Unit, University of Leeds, St. James’s University Hospital, Leeds, United Kingdom; and
Department of Microbiology, Joan and Joel Smilow Research Center, New York University School of Medicine, New York, NY 10016
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.
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1 This work was supported by the Veterans Affairs Center on AIDS and HIV Infection of the South Texas Veterans Health Care System and other awards from the National Institutes of Health to S.K.A. (R37046326, AI043279, and MH069270) and D.U. (A1054206, AI049131, and F32AI063975). S.K.A. is a recipient of the Elizabeth Glaser Scientist Award and the Burroughs Wellcome Clinical Scientist Award in Translational Research. S.M. was supported by the Merit Review Entry Program of the Department of Veterans Affairs.
2 The publisher or recipient acknowledges right of the U.S. government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.
3 L.M.A., S.E.V., and M.K. contributed equally to this study.
4 Address correspondence and reprint requests to Dr. Sunil K. Ahuja, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; E-mail address: ahujas{at}uthscsa.edu or Dr. Derya Unutmaz, Department of Microbiology, New York University School of Medicine, New York, NY 10016; E-mail address: derya.unutmaz{at}med.nyu.edu
5 Abbreviations used in this paper: ORF, open reading frame; UTR, untranslated region; Pr, promoter; CHART-PCR, chromatin accessibility real-time PCR; TF, transcription factor; qPCR, quantitative PCR; CNS, conserved noncoding sequence; NCNS, nonconserved noncoding sequence; Ct, cycle threshold; ChIP, chromatin immunoprecipitation; IVTT, in vitro transcription and translation; AGM, African Green Monkey; HDV, HIV-derived vector; siRNA, small interfering RNA.
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