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Journal of Virology, February 2001, p. 1842-1856, Vol. 75, No. 4
Department of Microbiology and Immunology,
The Pennsylvania State University College of Medicine, Hershey,
Pennsylvania 17033,1 and Department of
Veterinary Science, The Pennsylvania State University, University
Park, Pennsylvania 168022
Received 16 June 2000/Accepted 15 November 2000
Recent observations have shown two CCAAT/enhancer binding protein
(C/EBP) binding sites to be critically important for efficient human
immunodeficiency virus type 1 (HIV-1) replication within cells of the
monocyte/macrophage lineage, a cell type likely involved in transport
of the virus to the brain. Additionally, sequence variation at C/EBP
site I, which lies immediately upstream of the distal nuclear factor
kappa B site and immediately downstream of a binding site for
activating transcription factor (ATF)/cyclic AMP response element
binding protein (CREB), has been shown to affect HIV-1 long terminal
repeat (LTR) activity. Given that C/EBP proteins have been shown to
interact with many other transcription factors including members of the
ATF/CREB family, we proceeded to determine whether an adjacent ATF/CREB
binding site could affect C/EBP protein binding to C/EBP site I. Electrophoretic mobility shift analyses indicated that selected
ATF/CREB site variants assisted in the recruitment of C/EBP proteins to
an adjacent, naturally occurring, low-affinity C/EBP site. This
biophysical interaction appears to occur via at least two mechanisms.
First, low amounts of CREB-1 and C/EBP appear to heterodimerize and
bind to a site consisting of a half site from both the ATF/CREB and C/EBP binding sites. In addition, CREB-1 homodimers bind to the ATF/CREB site and recruit C/EBP dimers to their cognate weak binding sites. This interaction is reciprocal, since C/EBP dimer binding to a
strong C/EBP site leads to enhanced CREB-1 recruitment to ATF/CREB
sites that are weakly bound by CREB. Sequence variation at both C/EBP
and ATF/CREB sites affects the molecular interactions involved in
mediating both of these mechanisms. Most importantly, sequence
variation at the ATF/CREB binding site affected basal LTR activity as
well as LTR function following interleukin-6 stimulation, a treatment
that leads to increases in C/EBP activation. Thus, HIV-1 LTR ATF/CREB
binding site sequence variation may modulate cellular signaling at the
viral promoter through the C/EBP pathway.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.4.1842-1856.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Interaction between CCAAT/Enhancer Binding Protein and Cyclic
AMP Response Element Binding Protein 1 Regulates Human Immunodeficiency
Virus Type 1 Transcription in Cells of the
Monocyte/Macrophage Lineage
*
Corresponding author. Mailing address: Department of
Microbiology and Immunology (H107), Penn State College of Medicine, 500 University Dr., P.O. Box 850, Hershey, PA 17033. Phone: (717) 531-8258. Fax: (717) 531-5580. E-mail: bwigdahl{at}psu.edu.
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