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First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Japan
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been reported that various alterations of surface molecule expression of lymphocytes are induced by HHV-6 infection; that is, the expression level of CD3/TCR complex markedly decreases (13, 14) and de novo expression of CD4 is induced in CD4- T lymphocytes and NK cells after infection with HHV-6A (15, 16, 17). These alterations of surface molecule expression result in dysfunction of T lymphocytes and susceptibility to HIV-1 infection of CD4- lymphocytes (13, 14, 15, 16, 17). In addition to these findings, we have recently reported that the expression level of surface CXC chemokine receptor (CXCR) 4, which is a CXCR and a coreceptor for X4 HIV-1, markedly declines after infection with HHV-6A as well as HHV-6B (18). Down-regulation of CXCR4 has been reported also in HHV-7-infected cells by us and other investigators (18, 19). Down-regulation of CXCR4 resulted in impaired chemotaxis and a decreased level of elevation of the intracellular Ca2+ concentration in response to binding of the CXCR4 ligand, stromal cell-derived factor-1. Northern blot analysis of mRNAs extracted from HHV-6A- and HHV-6B-infected CD4+ T lymphocytes demonstrated a markedly decreased level of CXCR4 gene transcription compared with that in mock-infected cells, but the posttranscriptional stability was not significantly altered (18). These data indicate that down-regulation of CXCR4 in CD4+ T lymphocytes is induced by HHV-6 infection at the transcriptional level.
Understanding the mechanisms of down-regulation of CXCR4 would appear to be important, because manipulation of CXCR4 expression may lead to the development of novel means for protection against HIV infection. Recently, the structure of the promoter for the CXCR4 gene has been identified (20, 21, 22); this finding led us to study the mechanisms of transcriptional down-regulation of CXCR4 induced by HHV-6 infection. Our results demonstrated that impaired association between c-Myc, Max, and Mad results in increased DNA binding activity of YY1, which is a repressor of the CXCR4 promoter, in HHV-6-infected cells. On the basis of these findings, the significance of transcriptional down-regulation of this HIV-1 coreceptor, CXCR4, induced by HHV-6 infection is discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We used the U1102 strain of HHV-6A and the Z29 strain of HHV-6B. The viruses were grown in cord blood mononuclear cells that had been stimulated with PHA, as described previously (2). The CD4+ human T cell lines, JJHAN and MT-4, were cultured in RPMI 1640 medium supplemented with 10% FCS then infected with HHV-6A and HHV-6B, respectively, at an approximate multiplicity of infection of 1 50% tissue culture infective doses. HHV-6A- and HHV-6B-inoculated and mock-infected cells were cultured in a 5% CO2 incubator at 37°C until the cytopathic effect became detectable. Maximal cytopathic effect was usually detected after 4 days of virus inoculation.
Flow cytometric analysis
Expression of cell surface CXCR4 was examined by flow cytometric analysis using PE-conjugated anti-CXCR4 mAb (12G5; PharMingen, San Diego, CA). Cells to be used as unstained negative controls for CXCR4 were incubated with control PE-conjugated mouse monoclonal IgG (PharMingen).
Preparation of cell nuclear extracts and EMSA
The cells were washed with cold PBS and centrifuged. The cell
pellet was then resuspended in 400 µl of cold lysis buffer (10 mM
HEPES, pH 7.9, 0.1 mM EDTA, 1.0 mM DTT, 0.5 mM PMSF, 0.2 mM
Na3VO4, and 0.5% Nonidet
P-40) by gently pipetting, and incubated on ice for 15 min. The
centrifuge tube was then vortexed vigorously for 10 s and spun for
30 s. The nuclear pellet was suspended in 100 µl of cold protein
extraction buffer (10 mM HEPES, pH 7.9, 400 mM NaCl, 1.0 mM EDTA, 1.0
mM DTT, 1.0 mM PMSF, 0.2 mM
Na3VO4, and 10% glycerol),
vigorously vortexed for 15 min at 4°C, and centrifuged at 12,000
x g for 5 min at 4°C. The supernatant was stored at
-80°C until used as the nuclear extract. EMSA was conducted as
described by Schreiber et al. (23), with minor
modifications. The YY1 element
(5'-TAGCAAGGATGGACGCGCCACAGAGAGAC-3') from the promoter region of
the CXCR4 gene was used as a probe. The annealed
oligonucleotides were labeled by filling in their overhanging ends with
the Klenow fragment in the presence of
[
-32P]dCTP (3000 Ci/mol; Amersham Pharmacia
Biotech, Buckinghamshire, U.K.). The labeled DNA fragment was incubated
in a 40-µl final volume of reaction buffer (20 mM HEPES, pH 7.9, 50
mM KCl, 1 mM EDTA, 12% glycerol, 1 mM DTT, 2.5 µg poly[(dI)(dC)]
and 8 µg nuclear extract protein). After 20 min of incubation at room
temperature, the sample was subjected to 4% PAGE in 0.5x Tris-borate
EDTA. The gel was then dried and exposed to x-ray film. Competitive
experiments were performed using a 40-fold molar excess of the
corresponding unlabeled oligonucleotides, YY1 binding probe, or the
AP-1 binding probe (5'-CGGCTCCGGACTCACTACCGAACCA-3'). For the
supershift assay, 1 µg of specific Ab or rabbit polyclonal IgG was
added to the nuclear extract, which was incubated at room temperature
for 20 min before addition of the appropriate radiolabeled
oligonucleotide.
Construction of reporter plasmids
The promoter region of the CXCR4 gene was cloned from the genomic DNA by PCR and introduced into the luciferase expression plasmid, Pica Gene Vector Basic 2 (Toyo Ink, Tokyo, Japan). To facilitate subcloning in the expression plasmids, the primers used included the XhoI and the HindIII site at the 5' and 3' ends. All PCR amplifications were conducted using the antisense primer, 5'-ATTGAAGCTTCTCCAGATGCGGT-3', which encompasses the transcription start site (+76). Specific sense primers for amplification of the different promoter regions were: -334/+76; 5'-TCCACTCGAGCAAGGATGGAC-3', -313/+76; 5'-CGCCCTCGAGAGACGCGTTCCT-3', -186/+76; 5'-CGACCTCGAGCAAACAGCAGGGTC-3', -124/+76; 5'-CCTTCCTCGAGTCTGCCCCTCTC-3', -81/+76; 5'-CCTTCTCGAGCCCCGCCCCAGCG-3', -76/+76; 5'-AAAACTCGAGCGGCGCATGCGCC-3', -56/+76; 5'-GCATCTCGAGCGCTCGGAGCGTGTT-3'.
Luciferase assays
Transfection of 5 µg of the constructed plasmids and 0.5 µg of the sea-pansy luciferase expression plasmid pRL-SV40 (Toyo Ink) as an internal control, was performed by lipofection using 10 µl of DMARIE-C reagent (Life Technologies, Grand Island, NY) according to the manufacturer’s instructions. One hour after transfection, the cells were inoculated with HHV-6A and HHV-6B as described above. After 48 h, the cells were harvested, and luciferase activity and sea-pansy luciferase activity were assessed using a Pica Gene Dual Sea-Pansy Luminescence Kit (Toyo Ink) according to the manufacturer’s instructions and a luminometer (Lumi-counter 700; Microtec Nition, Chiba, Japan). Results are expressed as the ratio of luciferase activity to sea-pansy luciferase activity. To examine the effect of c-Myc overexpression on CXCR4 promoter activity, transient expression of c-Myc was performed using 5 µg of pcDNA3-c-myc and pcDNA3 as a control.
Overexpression of YY1 in JJHAN and MT-4 cells
For transfection of JJHAN and MT-4 cells with a YY1 expression plasmid, the cells were plated at a density of 4 x 105 cells per well in a 24-well plate and were allowed to recover overnight before transfection. A YY1 expression plasmid, pCMV-YY1, and a control plasmid, pCMV, were gifts from Dr. T. Shenk (Princeton University, Princeton, NJ) (24). Transfections of 5 µg pCMV-YY1 and pCMV were performed as described above. After 24 h, plates of JJHAN and MT-4 cells were fed with culture medium containing G418 (Life Technologies) at a concentration of 1600 and 500 µg/ml, respectively. Resistant clones were isolated and expanded over the next several weeks. After expansion, flow cytometric analysis was performed as described above.
Preparation of whole extracts
Cells were harvested after 4 days of virus inoculation, and the number of cells per sample was adjusted to 1 x 107. The cells were lysed at 4°C in 1 ml lysis buffer (1% Triton X-100, 150 mM NaCl, 20 mM HEPES, pH 7.3, 5 mM NaF, 1 mM Na3VO4, and 1 mM PMSF). After centrifugation at 12,000 x g for 15 min at 4°C, the supernatants were stored as whole extracts at -80°C until used.
Immunoprecipitation and Western blot analysis
To detect c-Myc associated with YY1, 10 µl of rabbit anti-YY1 polyclonal Ab (H-414; Santa Cruz Biotechnology, Santa Cruz, CA) was added to 1 mg of the whole extracts and incubated overnight at 4°C. The immune complexes were collected on protein A-Sepharose beads (Amersham Pharmacia Biotech) by incubating for 1 h at 4°C, washed with cold lysis buffer six times at 4°C, diluted with SDS sample buffer, and subjected to 10% SDS-PAGE. The separated proteins were transferred onto nitrocellulose membranes (Amersham Pharmacia Biotech). The filters were incubated in blocking buffer (20 mM Tris-HCl, pH 7.5, 500 mM NaCl, and 5% FCS) overnight at 4°C then incubated with rabbit anti-c-Myc Ab (N-262; Santa Cruz Biotechnology) for 1 h at room temperature. The filters were then washed and incubated with HRP-conjugated anti-rabbit IgG (Amersham Pharmacia Biotech). After washing, the blots were developed by an enhanced chemiluminescent detection system (ECL; Amersham Pharmacia Biotech). Similarly, the c-Myc/Max complex was detected by immunoprecipitation using rabbit anti-c-Myc Ab (N-262; Santa Cruz Biotechnology), and immunoblots were developed with rabbit anti-Max Ab (C-124; Santa Cruz Biotechnology). The Max/Mad complex was detected by immunoprecipitation using mouse anti-Mad 1 Ab (B-5; Santa Cruz Biotechnology), and immunoblots were developed with rabbit anti-Max Ab (C-124; Santa Cruz Biotechnology). For Western blot analysis alone, 30 µg of the whole extracts was subjected to 10% SDS-PAGE, and the following methods were the same as described above. Goat anti-human CXCR4 Ab (C-20; Santa Cruz Biotechnology) and rabbit anti-GAPDH Ab (Trevigen, Gaithersburg, MD) were used for this assay.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously reported that down-regulation of CXCR4 is induced by
HHV-6A and HHV-6B infection in peripheral blood
CD4+ T lymphocytes. As shown in Fig. 1
A, down-regulation of surface
CXCR4 was also detected in HHV-6A-infected JJHAN and HHV-6B-infected
MT-4 cell lines. Kinetics studies showed that down-regulation of
surface CXCR4 in HHV-6-infected cells was first detectable 2 days after
virus inoculation and became maximal at day 4 of infection (data not
shown). As we reported previously with regard to HHV-6-infected
peripheral blood CD4+ T lymphocytes
(18), the level of mRNA for CXCR4 was markedly decreased
in CD4+ T cell lines after infection with HHV-6A
and HHV-6B (Fig. 1B). To further confirm that
down-regulation of CXCR4 in HHV-6-infected cells is induced at the
transcriptional level and is not due to internalization of surface
CXCR4 into the cytoplasm, Western blot analysis using whole cell
lysates was performed. As shown in Fig. 1C, the expression
level of CXCR4 protein in CD4+ T cell lines
declined markedly after infection with HHV-6A and HHV-6B. These data
confirm our previous finding that down-regulation of CXCR4 in
HHV-6-infected cells is induced at the transcriptional level and
suggest that transcriptional down-regulation of CXCR4 is induced
ubiquitously by HHV-6 infection in various types of cells.
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To identify the promoter region involved in the down-regulation of
CXCR4 in HHV-6-infected cells, a series of 5' flanking sequences were
amplified by PCR and linked to the luciferase reporter gene. A series
of the constructs formed with progressive 5' deletions of the
CXCR4 promoter sequence was generated spanning bases
-334/+76, -313/+76, -186/+76, -124/+76, -81/+76, -76/+76, and
-56/+76. Each of the constructs was transfected into HHV-6- and
mock-infected cells, and luciferase activity was determined. As
reported previously (20), a YY1 binding site at around
-320 relative to the transcription start site appeared to be involved
in the negative regulation of CXCR4 transcription in
mock-infected cells (Fig. 2). The degree
of repression of CXCR4 promoter activity mediated by this
YY1 binding site was significantly higher in HHV-6-infected cells than
in mock-infected cells, suggesting that YY1 inhibits CXCR4
promoter activity through its binding to the CXCR4
promoter.
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To examine the role of YY1 in down-regulation of CXCR4,
CD4+ T cell lines, JJHAN and MT-4, were
transduced with a YY1 expression plasmid and a control plasmid. A
significantly increased level of YY1 protein expression was detected in
cells transduced with the YY1 expression vector compared with cells
transduced with the control vector and untreated cells (data not
shown). As shown in Fig. 3, overexpression of YY1 resulted in significant reduction of cell surface
CXCR4 expression. This finding confirmed the repressor activity of YY1
on the CXCR4 promoter.
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To compare the binding activity of YY1 to the CXCR4
promoter in HHV-6- and mock-infected cells, EMSA was performed using a
YY1-binding probe. As shown in Fig. 4, the density of the single band differed significantly between HHV-6-
and mock-infected cells. This DNA-binding protein was identified as
YY1, because the band was completely eliminated by excess unlabeled YY1
binding competitor, and addition of anti-YY1 Ab supershifted this
complex. Therefore, it appeared that the binding activity of YY1 to the
CXCR4 promoter was increased significantly in HHV-6-infected
cells compared with the binding activity in mock-infected cells,
suggesting that increased binding activity of YY1 to the promoter
results in down-regulation of CXCR4.
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Previous in vitro and in vivo studies revealed that c-Myc inhibits
YY1 activity by its direct association with YY1 (25, 26, 27).
This finding conversely suggests that decreased association of c-Myc
with YY1 would result in increased YY1 activity and led us to study the
alteration in association of c-Myc with YY1 in HHV-6-infected cells.
The whole cell extracts were immunoprecipitated with anti-YY1 Ab,
and the amounts of c-Myc in the immunocomplexes were determined by
Western blot analysis with anti-c-Myc Ab. As shown in Fig. 5, the levels of c-Myc associated with
YY1 were significantly decreased in HHV-6A-infected JJHAN cells and
HHV-6B-infected MT-4 cells, compared with mock-infected JJHAN cells and
mock-infected MT-4 cells, respectively. These findings support our
hypothesis that the increased binding activity of YY1 to the
CXCR4 promoter in HHV-6-infected cells might be a result of
decreased association of c-Myc with YY1.
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, overexpression of c-Myc increased the
CXCR4 promoter activity in JJHAN cells. This finding
strongly suggests that YY1-mediated down-regulation of CXCR4 is
inhibited by c-Myc.
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A). Next, the whole cell
extracts were immunoprecipitated with anti-Max Ab, and the amounts
of Mad in the immunocomplexes were determined by Western blotting with
anti-Mad Ab. As shown in Fig. 7B, the level of Mad
heterodimerized with Max was significantly decreased in HHV-6-infected
cells compared with the level in mock-infected cells. The same results
were obtained from triplicate runs of each immunoprecipitation
assay.
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To determine whether the altered associations among YY1, c-Myc,
Max, and Mad in HHV-6-infected cells are induced by the impaired
protein synthesis, we performed Western blot analysis using whole cell
lysates and Abs against these transcriptional factors. As shown in Fig. 8, the levels of synthesis of each of
YY1, c-Myc, Max, and Mad protein appeared to be unchanged after
infection with HHV-6. These findings strongly suggest that HHV-6
infection does not affect the protein syntheses of YY1, c-Myc, Max, or
Mad, but induces altered binding associations between these
transcription factors.
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On the basis of these data, we summarized the mechanisms of
down-regulation of CXCR4 in HHV-6-infected cells (Fig. 9). That is, HHV-6 infection mediates
decreased association of Max with Mad and increased association of Max
with c-Myc. These alterations result in decreased levels of the
YY1/c-Myc complex and consequent increased binding activity of YY1, a
negative regulator of CXCR4, to the CXCR4
promoter, resulting in inhibition of CXCR4
transcription.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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YY1 is a zinc finger transcription factor that is ubiquitously expressed and highly conserved among mammalian species (25). Depending on the promoter analyzed and on the cellular context, YY1 either stimulates or represses gene transcription. In addition, it has also been implicated in initiator function. In this study, a YY1 binding site around -320 relative to the CXCR4 transcription start site appeared to be important for suppression of CXCR4 promoter activity. Transfection of the YY1 expression vector into CD4+ T cell lines resulted in a reduction in the level of surface CXCR4 expression, supporting the previous report by Moriuchi et al. that YY1 is a repressor of CXCR4 transcription (28). The binding activity of YY1 to CXCR4 promoter was significantly increased in HHV-6-infected cells compared with mock-infected cells, strongly suggesting that increased binding activity of YY1 to the CXCR4 promoter is the main cause of CXCR4 down-regulation induced by HHV-6-infection. It has been reported that YY1 is physically associated with c-Myc in vitro and in vivo and that YY1 activity is inhibited by this interaction (25, 26, 27); that is, overexpression of c-Myc inhibits both the transcriptional activation and repression of YY1 in a dose-dependent manner (28). Conversely, reduction of the c-Myc level induces an increase in the level of free YY1, resulting in increased DNA-binding activity of YY1 (27). These previous findings were confirmed by our present study in which overexpression of c-Myc increased the activity of the CXCR4 promoter spanning a YY1 binding site. The present immunoprecipitation assays demonstrated that the association of c-Myc with YY1 decreased after HHV-6 infection. Because the overall protein levels of YY1 and c-Myc in CD4+ T lymphocytes remained unchanged after infection with HHV-6, impaired association of YY1 with c-Myc might result in an increase in the level of free YY1 that induces transcriptional down-regulation of CXCR4 in HHV-6-infected cells.
The transcription factor c-Myc does not homodimerize but heterodimerizes with a partner protein, Max, to regulate gene expression (29, 30). The complex of c-Myc/Max is capable of recognizing the core E box element, 5'-CACGTG-3'. In contrast, Max also heterodimerizes with the Mad family proteins to repress transcription and antagonize c-Myc (31, 32, 33, 34). All of the functional domains of c-Myc, Max, and Mad contain the basic helix-loop-helix leucine zipper. Because YY1 interacts with the C-terminal half of c-Myc, including the basic helix-loop-helix leucine zipper domain, YY1 may inhibit the dimerization of c-Myc with Max (35). In this study, it was found that the association of Mad with Max significantly decreased in HHV-6-infected cells. In addition, the association of Max with c-Myc appeared to increase after HHV-6 infection. The expression levels of c-Myc, Max, and Mad proteins remained unchanged in HHV-6-infected cells. Taken together, these observations strongly suggest that HHV-6 infection of CD4+ T lymphocytes affects the network of c-Myc, Max, and Mad, resulting in the augmentation of c-Myc-Max heterodimerization. Moreover, the increased association of c-Myc with Max may result in the decreased association of YY1 with c-Myc, as discussed above. It is well known that c-Myc expression affects various cellular functions, including apoptosis (36, 37). We previously reported that HHV-6 infection renders CD4+ T lymphocytes susceptible to apoptosis (38), suggesting that the increased association of c-Myc with Max may be one of the causes of CD4+ T lymphocyte apoptosis mediated by HHV-6 infection.
Because CXCR4 is an important coreceptor for HIV-1, this study seems to be important for understanding the pathogenesis of AIDS. It has recently been reported that Tax protein from human T-lymphotropic virus type I activates the CXCR4 promoter (39), and that influenza virus also up-regulates CXCR4 expression at a transcriptional level (40). These findings suggest that infectious agents such as human T-lymphotropic virus type I and influenza virus may contribute to disease progression in HIV-1-infected individuals by modulating HIV-1 coreceptor expression. Previous studies have demonstrated that HHV-6 can coinfect with HIV-1 and trans-activate the LTR of HIV-1 (10, 11, 12). In addition, it has been reported that CD4 expression is induced by HHV-6 infection of CD4- lymphocytes (15, 16, 17). On the basis of these findings, HHV-6 has also been considered a cofactor for progression of HIV-1 infection. However, our present data provide a possibility opposite to that proposed previously; that is, CXCR4 down-regulation mediated by HHV-6 may render CD4+ T lymphocytes resistant to infection with X4 HIV-1. This study also provides a new concept for developing protection against HIV-1 infection. In addition to its repressor function on CXCR4 transcription, YY1 has been reported to repress HIV-1 LTR transcription activity (41, 42). Because overexpression of YY1 did not affect the main characteristics of cells, including morphology, cell growth, and intracellular signaling through TCR (data not shown), the potential exists for gene therapy of AIDS focusing on cellular transcription factors such as YY1. In this study, we could not identify the components of HHV-6 that induce the impairment of the c-Myc/Max/Mad network. The mechanisms by which HHV-6 mediates the altered interaction between these transcription factors should be clarified by further studies. This information should shed light on our understanding of the detailed pathogenesis of HHV-6 infection and also provide a novel strategy for protection against HIV infection.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. M. Yasukawa, First Department of Internal Medicine, Ehime University School of Medicine, Shigenobu, Ehime 791-0295, Japan.
3 Abbreviations used in this paper: HHV, human herpesvirus; LTR, long terminal repeat; CXCR, CXC chemokine receptor.
Received for publication June 8, 2000. Accepted for publication October 30, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T lymphocytes by human herpesvirus 6: transcriptional induction of CD4 and susceptibility to HIV infection. J. Exp. Med. 181:1303.This article has been cited by other articles:
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