From the Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892 and the Division of Medical Virology, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Medical Sciences, Nagasaki 852-8523, Japan
Received for publication, September 13, 2000, and in revised form, November 2, 2000
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ABSTRACT |
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T cell activation can induce expression of CCR5,
a major coreceptor for macrophage-tropic (R5) human immunodeficiency
virus type 1 (HIV-1). Here we report that overexpression of the Oct-2 transcription factor and octamer coactivator BOB.1/OBF/OCA-B, both of
which are induced in T cells following T cell receptor signaling,
synergistically up-regulates CCR5 promoter activity via interaction
with an octamer motif on the promoter. We also show that the octamer
transcription factors can increase cell surface expression of CCR5 and
fusogenicity of the cells with R5 HIV-1 Env. These results suggest that
octamer transcription factors may play a critical role in the induction
of CCR5 expression on, and thereby susceptibility to, R5 HIV-1 of T
cells following antigenic stimulation.
Oct-2 is a transcription factor that binds specifically to octamer
motifs on its target promoter and/or enhancer regions including immunoglobulin and interleukin
(IL)1-2 genes (1). Oct-2 is
expressed predominantly in the B-cell lineage; however, recent studies
demonstrated that B cell-restricted gene regulation is dependent on B
cell-specific coactivator BOB.1/OBF/OCA-B (2-5). Expression of Oct-2
and BOB.1/OBF/OCA-B is also induced by antigenic stimulation of T cells
(6, 7). Thus, the octamer transcription system may play a role in gene
expression during T cell activation.
The CC chemokine receptor CCR5 is preferentially expressed in type 1 T
helper cells (8) and serves as a receptor for the CC chemokines
regulated upon activation, normal T cell expressed and secreted
(RANTES), macrophage inflammatory proteins 1 In this study, we demonstrate that the octamer motif plays a critical
role in the induction of CCR5 expression in activated T cells and that
octamer-mediated overexpression of CCR5 increases susceptibility of the
cells to R5 HIV-1 infection.
Plasmids--
Plasmid pGL-CCR5 WT contains the CCR5 promoter
sequence spanning Cells--
Peripheral blood mononuclear cells were obtained from
healthy volunteers (Department of Transfusion Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health and Red Cross
Blood Center in Nagasaki Prefecture, Japan), and CD4+ T
cells were isolated as described previously (25). Where indicated, CD4+ T cells were stimulated with phorbol 12-myristate
13-acetate (PMA) (1 µM) plus ionomycin (1 µM) or anti-CD3 plus anti-CD28 antibodies immobilized by
immunomagnetic beads for 8 h. CCR5-expressing PM1 lymphoid cells
were propagated as described previously (19).
RNA-PCR--
Total cellular RNA was extracted from cell pellets
according to the manufacturer's instructions (RNeasy Mini; Qiagen,
Santa Clarita, CA). RNA was reverse transcribed in a 50-µl reaction containing 50 mM Tris-HCl (pH 8.4), 75 mM KCl,
3 mM MgCl2, 10 mM dithiothreitol,
0.8 mM each dNTP, 1 unit of RNasin (Promega, Madison, WI),
100 pmol of random hexamer oligonucleotides, 2 µg of RNA sample, and
400 units of Moloney murine leukemia virus reverse transcriptase
(Promega). The reaction was incubated for 60 min at 37 °C, heated at
95 °C for 5 min, and quick-chilled on ice. The cDNA
corresponding to whole coding sequence of Oct-2 or BOB.1/OBF/OCA-B was
amplified by PCR for 30 cycles in a 50-µl reaction containing 1 µl
of cDNA product and 1.25 units of Taq BeadTM
Hot Start Polymerase (Promega). MgCl2 concentration in the
reaction was 3.0 mM for Oct-2 amplification and 2.0 mM for OCA-B amplification. Primers used for PCR were
5'-ATGTCTAAGCCCCTGGAG-3' (sense) and 5'-CATCAAGGCAGGTAAGGG-3'
(antisense) for Oct-2 and 5'-CACAGCTCCGGAGCAAGC-3' (sense) and
5'-CTAAAAGCCTTCCACAGAG-3' (antisense) for OCA-B. A thermal cycle
profile was denaturation for 45 s at 94 °C, annealing for 1 min
at 55 °C, and elongation for 1 min 30 s at 72 °C, followed by a final elongation at 72 °C for 7 min. Primers used for
amplification of CCR5 cDNA were 5'-TACCAGCCTCCGTATTTC-3' (sense)
and 5'-TTACTATTCCCTCACCTTACC-3' (antisense). Control amplification was
performed for Transfection and Transient Expression Assays--
Transfections
and luciferase assays for transient expression assays were performed as
described previously (26).
Flow Cytometric Analysis--
Cell surface expression of CCR5 or
CXCR4 was determined by staining cells with monoclonal anti-CCR5
antibody 2D7 phycoerythrin conjugate or anti-CXCR4 antibody 12G5
phycoerythrin conjugate (PharMingen, San Diego, CA), respectively, and
by analyzing in a FACScan (Becton Dickinson Immunocytometry, San Jose,
CA), as described previously (27).
Viruses and Fusion Assays--
Recombinant vaccinia viruses
(rVV) were propagated as described previously (27). rVV expressing
Oct-2 (vOct2) was a generous gift of Dr. P. C. van der Vliet (28).
Fusion assays were performed as described previously (28). In brief,
293T cells were seeded onto 60-mm diameter tissue culture plates,
transfected with 10 µg of an Env expression vector plasmid using
calcium phosphate method, infected with vCB21R (a rVV encoding the
lacZ gene under the control of T7 promoter) at a
multiplicity of infection of 10 on the following day, and served as
fusion effectors. Primary CD4+ T cells obtained from
healthy volunteers were infected with vTF7-3 (a rVV expressing T7 RNA
polymerase) along with vWT or vOct2 at a multiplicity of infection of
10 each and served as fusion targets. After a 10-h culture at 37 °C,
both fusion effectors (293T cells) and fusion targets (CD4+
T cells) were mixed and incubated at 37 °C for 6 h in the
presence of cytosine arabinoside, and the mixed cell culture lysates
were subjected to Activation of CD4+ T Cells Induces Expression of Oct-2
and BOB.1/OBF/OCA-B--
Since we have recently identified an octamer
motif on the CCR5 promoter, we wanted to investigate whether this motif
plays a role in CCR5 expression on CD4+ T cells, a target
for HIV-1. First, we examined whether T cell activation can induce
expression of Oct-2 (a B cell-specific octamer factor) and
BOB.1/OBF/OCA-B (a B cell-specific octamer coactivator). As shown in
Fig. 1, mRNA specific for Oct-2 and
BOB.1/OBF/OCA-B was amplified by reverse transcriptase-PCR in
CD4+ T cells treated with PMA plus ionomycin or anti-CD3
plus anti-CD28, stimuli mimicking T cell receptor signaling or
antigenic stimulation. As previously shown, CCR5 mRNA in activated
CD4+ T cells but not that in unstimulated cells was easily
detectable under the PCR conditions used (Fig. 1). Thus, these octamer
factors may be able to influence expression from octamer motif-bearing promoter (e.g. that for CCR5) in activated CD4+
T cells.
Overexpression of Oct-2 Up-regulates the CCR5 Promoter--
To
investigate whether octamer transcription factors can regulate CCR5
promoter activity, PM1 cells were transfected with pGL-CCR5 WT along
with various amounts of an expression vector for Oct-2. As shown in
Fig. 2A, overexpression of
Oct-2 up-regulated CCR5 promoter activity in a
dose-dependent manner. Furthermore, stimulation with PMA
plus ionomycin synergistically increased Oct-2-mediated transactivation
of CCR5 promoter (data not shown).
To determine whether an octamer motif on the CCR5 promoter is critical
for Oct-2-mediated activation of the promoter, the octamer motif was
mutated in plasmid pGL-CCR5 WT, and the construct was tested for its
reporter activity. Mutation of the octamer motif had minimal effect on
the CCR5 promoter activities induced by either GATA1 (Fig.
2C) or NF- Oct-2 and the Octamer Coactivator BOB.1/OBF.1/OCA-B Synergistically
Up-regulate the CCR5 Promoter--
The octamer coactivator
BOB.1/OBF/OCA-B plays a critical role in octamer-dependent
transcriptional activation in B cells and activated T cells (2-5, 7).
To determine whether BOB.1/OBF/OCA-B plays a crucial role in the
induction of CCR5 promoter activity, Oct-2 and BOB.1/OBF/OCA-B were
expressed in PM1 cells individually or in combination. Either Oct-2 or
BOB.1/OBF/OCA-B alone had a minimal effect on the CCR5 promoter
activity at the concentration used; however, expression of both factors
markedly enhanced the promoter activity (Fig.
3).
Overexpression of Oct-2 Up-regulates Cell Surface Expression of
CCR5--
As shown above, octamer transcription factors can
up-regulate the CCR5 promoter. To demonstrate whether cell surface
expression of CCR5 is also up-regulated by octamer transcription
factors, we overexpressed Oct-2 by infecting CD4+ T cells
with vOct2 (a rVV expressing Oct-2), and determined cell surface CCR5
expression by flow cytometry. CCR5 expression in CD4+ T
cells that were infected with vWT (a wild type rVV) was modest (3%)
but was significantly induced (30%) by infection of CD4+ T
cells with vOct2 (Fig. 4A).
Thus, overexpression of Oct-2 appears to induce cell surface expression
of CCR5. In contrast, overexpression of Oct-2 did not induce cell
surface CXCR4 expression (Fig. 4B).
Overexpression of Oct-2 Increases Fusogenicity of Peripheral Blood
Lymphocytes with R5 HIV-1 Env--
Levels of CCR5 expression
appear to correlate well with infectability of CD4+ T cells
by R5 HIV-1 (18). We therefore investigated whether up-regulation of
CCR5 expression by Oct-2 can increase efficiency of fusion/entry of R5
HIV-1. Primary CD4+ T cells (fusion targets) were infected
with vWT or vOct2 as well as vTF7-3 (expressing T7 RNA polymerase).
293T cells (fusion effectors) were transfected with a plasmid
expressing HIV-1 JR-FL (R5) Env or HIV-1 HXB2 (X4) Env or a plasmid
expressing AMLV Env and infected with vCB21R (encoding the
lacZ gene under the control of the T7 promoter). Fusion
efficiency between the two cells was assayed by In this study, we have demonstrated that octamer transcription
system can up-regulate expression of CCR5 at the promoter level, leading to increased efficiency of R5 HIV-1 entry into CD4+
T cells. Levels of CCR5 expression appear to correlate well with infectability of CD4+ T cells by R5 HIV-1 (18), and
expression of CCR5 appears to be highly regulated (9, 30-36).
Activation with phytohemagglutinin and IL-2 increases expression of
CCR5 on lymphocytes (30). Treatment of macrophages with IL-10,
granulocyte-macrophage colony-stimulating factor, or macrophage
colony-stimulating factor up-regulates CCR5 expression (31, 32), while
CCR5 expression on macrophages is down-regulated by treatment with
IL-4, IL-13, or prostaglandin E2 (32, 33). Furthermore,
CCR5 expression in cells of monocyte/macrophage lineage appears to
increase upon differentiation into a more mature phenotype (34).
At the promoter level, several transcription factors have been
demonstrated to regulate CCR5 expression, including p65 (RelA) (35) and
GATA-1 (36). The present study has extended our understanding of
molecular mechanism of regulation of CCR5 promoter activity by
demonstrating that Oct-2 and BOB.1/OBF/OCA-B, both of which are induced
by antigenic stimulation of T cells (6, 7), synergistically
transactivate the CCR5 promoter.
Antigenic stimulation has been associated with increased viral load in
HIV-infected individuals (37, 38). A recent study has demonstrated that
most HIV-1 strains isolated from patients who were stimulated with
tetanus toxoid, a common recall antigen, were R5 (39), suggesting that
antigenic stimulation may provide a favorable environment for
replication of R5 HIV-1. Therefore, one mechanism that renders
antigenically stimulated CD4+ T cells highly susceptible to
HIV-1 infection is probably up-regulation of CCR5 expression by the
octamer transcription system. Further investigation to delineate the
molecular and cellular mechanisms that regulate expression of HIV
coreceptors is warranted.
INTRODUCTION
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
and 1
(9-11). CCR5
is also essential for cellular entry of macrophage-tropic (R5) human
immunodeficiency virus type 1 (HIV-1) (12-17), and levels of its
expression appear to be critical for infectability by R5 HIV-1 (18). We
have recently cloned and characterized the promoter region of CCR5 and
identified an octamer motif on the promoter region (19); however, it
remained to be determined whether the octamer motif has a role in the
regulation of CCR5 expression on T cells or macrophages, the two major
target cells for HIV-1.
EXPERIMENTAL PROCEDURES
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
770 to +61 relative to the transcription start site
(19), followed by the luciferase reporter gene. Plasmid pGL-CCR5
Oct has mutations (shown in boldface letters below) on the octamer motif
(indicated by underline) around
230 relative to the transcription start site (ATGAATGTAAATGTTC
ATGAATGTATACGTTC), which was generated by
PCR-oriented site-directed mutagenesis (20). Plasmids pCG-Oct2,
pCGN-OCA-B, and their parent plasmid pCGN were generous gifts of W. Herr (Cold Spring Harbor Laboratory) (21, 22). Plasmid pMT-GATA1 and
its parent plasmid pMT2T were kindly provided by S. H. Orkin
(Harvard Medical School) (23); plasmid pMT-p65 (which encodes the
NF-
B p65 subunit) was a gift of U. Siebenlist (NIAID, National
Institutes of Health) (24). Plasmids encoding Env from HIV-1 R5 strain
JR-FL or X4 strain HXB2 or Env from amphotropic murine leukemia virus
(AMLV) were kindly provided by N. Landau (Aaron Diamond AIDS Research
Center) (14).
-actin cDNA. Amplification was performed at
denaturation for 45 s at 94 °C, annealing for 1 min at
50 °C, and elongation for 1 min at 72 °C for 20 cycles, followed
by a final elongation at 72 °C for 7 min. The PCR products (10 µl
for Oct-2, BOB.1/OBF/OCA-B, or CCR5 and 2 µl for
-actin) were
resolved on a 1% agarose gel and visualized by ethidium bromide staining.
-galactosidase assays.
RESULTS
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Fig. 1.
Induction of Oct-2 and BOB.1/OBF.1/OCA-B
mRNA expression by activation of CD4+ T cells.
CD4+ T cells obtained from normal volunteers were either
unstimulated (Control) or stimulated with PMA plus ionomycin
or anti-CD3 plus anti-CD28 (Anti-CD3/CD28). Total RNA
prepared from these cells was subjected to reverse transcriptase-PCR to
amplify cDNA for CCR5, Oct-2, BOB.1/OBF.1/OCA-B, or
-actin.
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Fig. 2.
The octamer motif on the CCR5 promoter
mediates Oct-2-induced transactivation. A, 20 million
PM1 cells were transfected with 20 µg of pGL-CCR5 WT along with the
indicated amount of pCG-Oct-2. Total input DNA amounts were adjusted
equally by adding pCGN (parent plasmid). Luciferase assays in the
transfected cell lysates were performed 40 h after transfection.
Results are reported as means ± S.E. from four independent
experiments. B and C, 20 million PM1 cells were
transfected with 20 µg each of the plasmids indicated at the
bottom. Results are reported as means ± S.E. from
three independent experiments.
B p65 (data not shown); however, it almost
abolished the promoter activity induced by Oct-2 (Fig. 2B),
indicating that the octamer motif plays a crucial role in the
Oct-2-induced activity of the CCR5 promoter.
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Fig. 3.
Oct-2 and the octamer coactivator
BOB.1/OBF.1/OCA-B synergistically up-regulate the CCR5 promoter.
20 million PM1 cells were transfected with 20 µg each of pGL-CCR5 WT
or pGL-CCR5 Oct along with 10 µg each of the plasmids indicated at
the bottom, and luciferase assays were performed 40 h
after transfection. Results are reported as means ± S.E. from
four independent experiments.
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Fig. 4.
Overexpression of Oct-2 increases cell
surface expression of CCR5. Primary CD4+ T cells were
infected with either vWT (a wild type vaccinia vector) or vOct-2 (a
vaccinia vector expressing Oct-2) overnight, stained with either
anti-CCR5 (A) or anti-CXCR4 (B)
phycoerythrin-conjugate (shown in solid lines),
and analyzed in FACScan. Staining with isotype control is shown in
broken lines, with shaded areas.
Results are representative of three independent experiments.
-galactosidase
activity in the mixed cell culture lysates. Overexpression of Oct-2
markedly increased fusogenicity of CD4+ T cells with R5
HIV-1 Env (Fig. 5), and pretreatment of
the cells with AOP-RANTES (a CCR5 ligand) abolished R5 HIV-1
Env-mediated cell fusion (data not shown), indicating that CCR5 is
required for the Oct-2-mediated effect. Fusogenicity with X4 HIV-1 Env was modestly increased upon overexpression of Oct-2 at a level comparable with that with unrelated AMLV Env (Fig. 5), suggesting that
Oct-2 has no effect on CXCR4-mediated cell fusion per se, although it may somehow increase cellular fusogenicity in a nonspecific manner. Thus, the octamer transcription system may play a critical role
in R5 HIV-1 infection by up-regulating expression of CCR5.
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Fig. 5.
Overexpression of Oct-2 increases fusogenic
activity of the cells with R5 HIV-1 Env. Primary CD4+
T cells (fusion targets) were infected with vWT or vOct-2 as well as
vTF7-3 (expressing the T7 RNA polymerase). 293T cells (fusion
effectors) were transfected with a plasmid expressing R5 HIV-1 (JR-FL)
Env, X4 HIV-1 (HXB2) Env, or AMLV Env and infected with vCB21R
(encoding the lacZ gene under the control of the T7
promoter). The two sets of cells were mixed in the presence of cytosine
arabinoside, and -galactosidase activity in the infected cell
lysates was determined 4 h after mixing. The fusion index
indicates
-galactosidase activity in vOct2-infected cultures
relative to that in vWT-infected cultures. Results are means ± S.E. from three independent experiments.
DISCUSSION
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EXPERIMENTAL PROCEDURES
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DISCUSSION
REFERENCES
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ACKNOWLEDGEMENTS |
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We thank Anthony S. Fauci for helpful discussions and for reviewing the manuscript and Hiroaki Mitsuya for encouragement and support. We also thank P. C. van der Vliet, W. Herr, S. H. Orkin, U. Siebenlist, E. Berger, and N. Landau for reagents and K. Iijima and M. Yokoyama for graphic work and technical assistance.
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FOOTNOTES |
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* This work was supported in part by grants provided by a Research for the Future Program (JSPS-RFTF97L00705) of the Japan Society for the Promotion of Science and by the Ichiro Kanehara Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The two authors contributed equally to this work.
§ To whom correspondence should be addressed: Dept. of Pediatrics, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Tel.: 81-95-849-7297; Fax: 81-95-849-7301; E-mail: hiromori@net.nagasaki-u.ac.jp.
Published, JBC Papers in Press, November 8, 2000, DOI 10.1074/jbc.M008391200
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ABBREVIATIONS |
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The abbreviations used are: IL, interleukin; RANTES, regulated upon activation, normal T cell expressed and secreted; HIV, human immunodeficiency virus; PCR, polymerase chain reaction; AMLV, amphotropic murine leukemia virus; PMA, phorbol 12-myristate 13-acetate; rVV, recombinant vaccinia virus(es).
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