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.
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.
Mummidi
Srinivas
S
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, USA.
Adams
Lisa M
LM
VanCompernolle
Scott E
SE
Kalkonde
Mrunal
M
Camargo
Jose F
JF
Kulkarni
Hemant
H
Bellinger
Adam S
AS
Bonello
Gregory
G
Tagoh
Hiromi
H
Ahuja
Seema S
SS
Unutmaz
Derya
D
Ahuja
Sunil K
SK
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D005091:Exons; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism*; D050813:Octamer Transcription Factor-2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D019713:Receptors, CCR5 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; D012333:RNA, Messenger; D019713:Receptors, CCR5