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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4521-4528
RAPID COMMUNICATION
Progressive and Persistent Downregulation of Surface CXCR4 in
CD4+ T Cells Infected With Human Herpesvirus 7
By
Paola Secchiero,
Davide Zella,
Oxana Barabitskaja,
Marvin S. Reitz,
Silvano Capitani,
Robert C. Gallo, and
Giorgio Zauli
From the Institute of Human Virology, University of Maryland,
Baltimore, MD; and the Human Anatomy Section, Department of Morphology
and Embriology, University of Ferrara, Ferrara, Italy.
 |
ABSTRACT |
We have previously shown that infection of CD4+ T
lymphocytes with the T-lymphotropic human herpesvirus 7 (HHV-7)
downregulates surface CD4, which represents the high-affinity receptor
for HHV-7. In this study, we report that HHV-7 infection also causes a
progressive loss of the surface CXC-chemokine receptor 4 (CXCR4) in
CD4+ T cells, accompanied by a reduced intracellular
Ca2+ flux and chemotaxis in response to stromal
cell-derived factor-1 (SDF-1), the specific CXCR4 ligand.
Moreover, CXCR4 is downregulated from the surface of HHV-7-infected T
cells independently of CD4. Because intracellular CXCR4 antigen and
mRNA levels are unaffected in productively HHV-7-infected cells, the
downregulation of CXCR4 apparently does not involve a transcritional
block. Since CXCR4 functions in association with CD4 to permit entry of
several human immunodeficiency virus (HIV) isolates, the potential of
HHV-7 to persistently downregulate the surface expression of CXCR4 may provide novel strategies for limiting HIV infection.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
THE 7-TRANSMEMBRANE G-protein-coupled
CXC-chemokine receptor 4 (CXCR4) is known to be expressed in all
hematopoietic cells, starting from immature CD34+
hematopoietic progenitors and including CD4+ and
CD8+ T-lymphocyte subsets.1-8 It has been shown
that CXCR4 plays an essential role as a coreceptor for the T-cell
line-adapted isolates of human immunodeficiency virus (HIV), which are
highly cytopathic and typically emerge in the late stages of HIV
disease.9,10 Because in vitro pretreatment with the
high-affinity ligand for CXCR4, stromal cell-derived factor-1
(SDF-1), inhibits the entry of these viruses into CD4+ T
cells,11-13 the issue of CXCR4 modulation and subcellular
trafficking has recently raised considerable attention.
CXCR4 undergoes efficient but transient endocytosis after interaction
with SDF-1 or treatment with phorbol esters.14-16 In CD4+ T lymphocytes, it appears to respond to similar
modulatory signals as CD4,3,16 and it has been proposed
that comodulation of CXCR4 and CD4 may play a role in regulating the
activity of CD4+ T cells. However, the different
constitutive endocytosis rates of CD4 and CXCR4, expressed on the SupT1
CD4+ T-lymphoblastoid cell line, and the selective
SDF-1-induced downmodulation of CXCR4 but not of CD4,14
rather suggest that these two proteins do not normally form stable
associations. A complex of CD4 and CXCR4 is likely to be induced by the
presence of HIV envelope gp120 protein.17,18
Because human herpesvirus 7 (HHV-7) shows a selective tropism for
CD4+ T lymphocytes19,20 and induces an abrupt
downregulation of CD4 antigen,20-22 we investigated whether
CXCR4 expression could be affected by HHV-7.
| |
MATERIALS AND METHODS |
Cells.
The CD4+ human T-cell line SupT1 (AIDS Research and
Reference Reagent Program, Manassas, VA) and a CD4
derivative of SupT1 called BC7 (generously provided by Dr J.A. Hoxie,
University of Pennsylvania, Philadelphia, PA)23 were routinely cultured in RPMI 1640 (GIBCO BRL, Gaithersburg, MD) containing 10% fetal calf serum (GIBCO BRL). Primary CD8-depleted and/or -enriched CD4+ T cells were derived from the
peripheral blood of healthy blood donors, by negative immunomagnetic
selection, and phytohemagglutinin (PHA)/interleukin-2 (IL-2)-activated
as previously described.24
Viral infections.
The HHV-7 isolates and the preparation procedures of viral stocks have
been previously described.20,25 Briefly, HHV-7 infections of both SupT1 and primary cells were performed by incubation with 0.45-µm-filtered infectious supernatants obtained from
HHV-7-infected SupT1 cells. Supernatants from uninfected SupT1 cells
were used for mock infections. For inhibition assays, target cells were preincubated for 30 minutes at room temperature with SDF-1 (2.5 µg/mL), 12G5 anti-CXCR4 monoclonal antibody (MoAb; 25 µg/mL), or
control mouse IgG2a (25 µg/mL) (all from Pharmingen, San Diego, CA).
After the addition of HHV-7 inocula (MOI = 0.01), cells were maintained
in the presence of SDF-1 or of the indicated antibodies for an
additional 40 hours, at which time cells were harvested and used for
RNA extraction (see below).
The occurrence of a productive HHV-7 infection was monitored by (1)
indirect immunofluorescence staining on acetone-fixed cells by using a
specific HHV-7 MoAb (5E1 MoAb; generously provided by Prof E. Campadelli-Fiume, University of Bologna, Bologna,
Italy),26,27 as previously described24; and (2)
HHV-7 reverse transcriptase-polymerase chain reaction
(RT-PCR), by using H7 and H8 primers28 that
amplify the HHV-7 U10 ORF.
Infection of SupT1 cells with HIV-1(IIIB) was performed as
described20 by using viral inocula derived from
HIV-1(IIIB)-infected H9 T-cells. HIV-1 infection was monitored by
serial determinations of HIV-1 p24 antigen released into the culture
supernatant (p24 ELISA Kit; DuPont-Merck Pharmaceutical Co, Wilmington,
DE) and visual inspection for syncytia formation.
Flow cytometry analysis.
Aliquots of 1.5 × 106 cells were subjected to single-
or multiple-label staining to examine the presence of surface
and/or intracellular Ags, as described
previously.22 CXCR4 expression was analyzed either by
indirect staining using 12G5 anti-CXCR4 MoAb (Pharmingen) followed by
fluorescein isothiocyanate (FITC)-conjugated goat
antimouse IgG or by using the phycoerythrin
(PE)-conjugated anti-CXCR4 MoAb (Pharmingen). The
expression of CD4 was analyzed by using either FITC-conjugated (Becton
Dickinson, San Jose, CA) or PE-conjugated anti-CD4 MoAb (Pharmingen).
CD3 expression was analyzed by using the Cy5-PE-conjugated MoAb (Becton
Dickinson). Briefly, surface staining was performed in 200 µL of
phosphate-buffered saline containing 1% fetal calf serum at 4°C
for 30 minutes.
For the specific detection of intracellular CXCR4, SupT1 cells were
pretreated with 20 µL of unconjugated anti-CXCR4 MoAb for 1 hour at
4°C to saturate surface CXCR4 before the fixing procedure. On the
other hand, for the simultaneous detection of surface CXCR4 and
intracellular CXCR4, SupT1 cells were first incubated with the
anti-CXCR4 MoAb followed by incubation with FITC-goat antimouse IgG.
Cells were then fixed in 2% paraformaldehyde and permeabilized with
0.2% Triton X100, as described previously.22 Intracellular
staining was then performed by using the PE-conjugated anti-CXCR4 MoAb.
Nonspecific fluorescence was assessed by using irrelevant
isotype-matched MoAbs (Becton Dickinson and/or Pharmingen). After staining procedures, samples were analyzed using a FACSCalibur flow cytometer (Becton Dickinson).
Calcium measurement.
Agonist-dependent increase in cytoplasmic Ca2+ was
determined as described.29,30 Briefly, aliquots of
106 cells were loaded with Fluo-3 reconstituted with
Pluronic F-127 (Molecular Probes, Eugene, OR) for 20 minutes at
37°C. After incubation, the samples were washed once with RPMI and
resuspended in 1 mL of the same medium. Data were acquired with a
FACSCalibur, with excitation at 488 nm. Cells were gated based on
forward and side scatter properties. After 20 seconds, SDF-1
(Pharmingen) or ionomycin (Sigma Chemicals, St Louis, MO) was added by
using a magnetic device, and calcium mobilization was determined by a
two-parameter density-plot measuring linear emission at 550 nm in the
FL-1 window for the gated cell population over time.
Chemotaxis assay.
Cell migration assays were performed as described.11
Briefly, uninfected and HHV-7-infected cells were resuspended in RPMI 1640 medium plus bovine serum albumin (1 mg/mL). The cell density was
adjusted to 5 × 106 cells/mL and 100 µL of the cell
suspension was added to the top chamber of a 24-Transwell apparatus
(5-µm pore size; Costar, Cambridge, MA). RPMI 1640/bovine serum
albumin containing various concentrations of the recombinant SDF-1
was added to the bottom chamber of the Transwell. After 3 hours of
incubation at 37°C, the cell numbers in the bottom chamber were
counted in a FACSCalibur, and percentages of the transmigration were
determined for each concentration of SDF-1, after subtraction of the
background (absence of SDF-1) transmigration.
RNA analysis.
RNA purification from uninfected and HHV-7-infected cells was
performed using the SV total RNA isolation system (Promega, Madison,
WI) following the manufacturer's protocol. Synthesis of first strand
cDNA and amplification were performed using the Access RT-PCR system
(Promega) following the manufacturer's protocol. As a control for DNA
contamination, equal amounts of RNA were used for PCR without template
retrotranscription. The resulting PCR products were separated on 2%
Seakem GTG agarose gel (FMC BioProducts, Rockland, ME). Primers and
reaction conditions for the amplification of HHV-7 U10
ORF28 (PCR product, 186 bp), CXCR430 (PCR
product, 430 bp), and  -actin (PCR product, 661 bp; Stratagene, San
Diego, CA) were as described previously.
| |
RESULTS |
Downregulation of surface CXCR4 expression in CD4+ T
cells after HHV-7 infection.
The levels of surface CXCR4 in the SupT1 lymphoblastoid
CD4+ T-cell line
(Fig 1A and
B) and in primary T lymphocytes (Fig 1C) were evaluated by flow
cytometry at various time points after HHV-7-infection, using the 12G5
anti-CXCR4 MoAb, either alone (Fig 1A) or in combination with anti-CD4
MoAb (Fig 1B and C). 12G5 binding was progressively reduced in
HHV-7-infected SupT1 cells compared with uninfected controls (Fig 1A).
Moreover, double-staining performed with anti-CXCR4 plus anti-CD4 MoAb
showed the presence of four distinct cell populations
(CXCR4+/CD4+,
CXCR4+/CD4,
CXCR4/CD4+, and
CXCR4/CD4; Fig 1B), clearly
indicating that the two antigens were downmodulated by HHV-7
independently. On the other hand, CD11 and CD45LCA surface markers were
unaffected by HHV-7 infection (data not shown). A marked decrease of
both CXCR4 and CD4 surface antigens, but not of CD3, was also observed
in CD8-depleted primary T lymphocytes after infection with HHV-7 (Fig
1C).
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| Fig 1.
Effect of HHV-7 and HIV-1 infection on surface CXCR4
expression in CD4+ T cells evaluated by flow cytometry.
In (A) and (B), progressive downregulation of surface CXCR4 expression
in HHV-7-infected SupT1 cells. In (B), surface CXCR4 was analyzed in
combination with surface CD4. In (C), surface CXCR4 was analyzed either
alone (top panels) or in combination with surface CD3 (middle panels)
and surface CD4 (bottom panels) in CD8+-depleted primary
cells, either uninfected or infected with HHV-7 (8 days PI). In (D),
surface CXCR4 was analyzed in combination with surface CD4 in SupT1
cells, either uninfected or infected with HIV-1 (12 days PI). Data
shown in (A) through (D) are representative of at least three separate
experiments. Horizontal axis (logarithmic scale), relative surface
CXCR4 expression detected by PE fluorescence intensity (in [A]
through [D]). Vertical axis, relative cell number, isotype-matched
control antibody staining, CD4 expression detected by FITC fluorescence
intensity or CD3 expression detected by Cy5-PE fluorescence intensity,
as indicated. Percentages of cells in the respective quadrants are
indicated. Representative negative controls, constituted by cells
stained with irrelevant isotype-matched MoAb, are shown in the top
panels of (A) and (B).
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In contrast, infection of SupT1 cells with HIV-1(strain IIIB) resulted
in drastic downregulation of CD4, comparable to that observed in
HHV-7-infected cells, but with no significant reduction in 12G5
reactivity (Fig 1D).
Because the experiments described above could not distinguish between
loss or surface CXCR4 and blocking of the 12G5 epitope, we next
evaluated the intracellular Ca2+ flux and chemotaxis in
response to SDF-1. To avoid the possibility that dead cells and cell
debris could interfere with these biological assays in both uninfected
and HHV-7-infected cultures, analysis was performed on viable cells
gated on the basis of forward and side scatter properties. At day 4 postinfection (PI), HHV-7-infected SupT1 cells showed a reduction in
the Ca2+ flux mediated by SDF-1 with respect to
uninfected cells (Fig 2A). On the other
hand, both uninfected and HHV-7-infected SupT1 cells responded in a
similar fashion to a nonspecific agonist, such as the Ca2+
ionophore ionomycin (Fig 2A), thus confirming that the reduced Ca2+ flux observed in HHV-7-infected cells in response to
SDF-1 was specific.
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| Fig 2.
Mobilization of calcium (A) and chemotaxis (B) of
uninfected and HHV-7-infected SupT1 cells in response to SDF-1.
HHV-7-infected cultures were analyzed at days 4 (A) or 6 (B) PI. (A)
shows transient intracellular calcium flux in response to SDF-1 (40 ng/mL; top panels) or to ionomycin (100 ng/mL; bottom panels). Data are
representative of three independent experiments. In (B), chemotaxis was
analyzed by using Transwells after induction with the indicated
concentration of SDF-1. Data are expressed as the percentage of
input cells transmigrated. The mean ± SD of three independent
experiments is shown.
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In a chemotactic assay, HHV-7-infected SupT1 cultures showed a cell
migration rate significantly (P < .01) lower than those uninfected (Fig 2B).
Unaffected levels of intracellular CXCR4 protein and mRNA in
HHV-7-infected cultures.
Having previously demonstrated that HHV-7 affects the expression of its
primary receptor, CD4, via multiple mechanisms,22 including
reduction of the de novo CD4 synthesis, we next evaluated the
intracellular levels of CXCR4 in HHV-7-infected and uninfected cells
by indirect immunofluorescence shown by flow cytometry
(Fig 3A). At day 8 PI, when greater than
50% of surface CXCR4 was already lost in HHV-7-infected cells,
all cells still stained positively for intracellular CXCR4 and the
fluorescence intensity of intracellular CXCR4 was only modestly
decreased in comparison to uninfected controls. Moreover,
analysis of CXCR4 mRNA by semiquantitative RT-PCR unequivocally
demonstrated that HHV-7 infection did not affect the levels of CXCR4
mRNA (Fig 3B).
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| Fig 3.
Analyses of intracellular CXCR4 protein and CXCR4 mRNA
content of uninfected and HHV-7-infected SupT1 cells. (A) Flow
cytometric analysis of intracellular CXCR4, either alone (top panels)
or in combination with surface CXCR4 (bottom panels), in uninfected and
HHV-7-infected (8 days PI) SupT1 cells. Horizontal axis, relative
intracellular CXCR4 expression detected by PE fluorescence intensity;
vertical axis, isotype-matched antibody staining or relative surface
CXCR4 expression detected by FITC fluorescence intensity. Percentages
of cells in the respective quadrants are indicated. The profile of the
negative controls, represented by SupT1 cells stained with irrelevant
isotype matched MoAb, were as shown in Fig 1B (top panel). The data are
representative of four experiments from separate infections. (B)
Semiquantitative RT-PCR specific for CXCR4 mRNA was applied to analyze
CXCR4 mRNA levels in HHV-7-infected SupT1 cultures (8 days PI) as
compared with the uninfected cells. -Actin amplification was used to
confirm comparability of the samples. Equivalent amounts of RNA
extracted from uninfected and HHV-7-infected cells were used for 1:3
limiting step dilution (lanes 1 through 4) before RT-PCR with the CXCR4
and -actin primers. Ethidium bromide-stained agarose gel of RT-PCR
products is shown. Lanes  , amplification of the indicated RNA
template performed before RT; lane BL, blank.
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Inibition of HHV-7 infection by SDF-1.
Cellular receptors for enveloped viruses are characteristically
downregulated from the cell surface after productive infection, rendering infected cells resistant to superinfection by viruses that
use the same receptor.31 Indeed, the observation that CD4 was selectively downregulated on HIV-1-infected cells as well as on
HHV-7-infected cells provided the initial evidence that CD4 was a
receptor for these viruses.20,32 Given the evidence that
CXCR4 was downregulated during HHV-7 infection, we used SDF-1 to
determine if CXCR4 was also serving as a component of the receptor for
HHV-7. As shown in Fig 4A, preincubation
with SDF-1 (2.5 µg/mL) led to a drastic reduction of surface CXCR4
associated with a complete block of expression of specific HHV-7 mRNA
transcripts, evaluated 40 hours PI. On the other hand, preincubation
with 12G5 MoAb (25 µg/mL) or control IgG2a (25 µg/mL) failed to
inhibit infection, indicating that the epitope recognized by 12G5 MoAb is not essential for HHV-7 entry. Similar results have been previously reported for several HIV-1 and HIV-2 isolates.33
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| Fig 4.
Effect of SDF-1 on HHV-7 infection. (A)
SDF-1-dependent CXCR4 downmodulation (left panel) and inhibition of
HHV-7 infection (right panel). SupT1 cells were preincubated with
SDF-1 (2.5 µg/mL) for 30 minutes at room temperature and then
either remained uninfected or inoculated with HHV-7. Before
HHV-7-infection, surface CXCR4 was analyzed by flow cytometry (left
panel). Horizontal axis, surface CXCR4 expression detected by PE
fluorescence intensity; vertical axis, relative cell number. Negative
control (Cont) is represented by cells stained with irrelevant
isotype-matched control MoAb. The right panel shows HHV-7 expression
determined by specific RT-PCR in SupT1 cells preincubated with nothing
(lane 1), 2.5 µg/mL of SDF-1 (lane 2), 25 µg/mL of control mouse
IgG2a (lane 3), and 25 µg/mL of 12G5 anti-CXCR4 MoAb (lane 4).
Equivalent amounts of RNA, extracted at 40 hours PI, were used as
template for RT-PCR using either HHV-7-specific primers (U10 ORF) or
-actin primers. Control reaction, performed by amplifying the same
RNA samples before RT (RT) is also shown; lane BL, blank. The data
are representative of three separate experiments. (B)
CD4+ SupT1 or CD4 BC7 cells were
inoculated with HHV-7 and monitored for HHV-7 expression and
replication by specific viral RT-PCR at 40 hours PI (left panels) and
by indirect immunofluorescence at 8 days PI (microphotographs). For
RT-PCR, equivalent amounts of RNA samples, before () and after (+)
RT, were used as template for the amplification reactions. PCR products
for HHV-7/U10 ORF and -actin are shown; lane BL, blank.
Immunofluorescence microscopy was performed as described by using the
5E1 HHV-7-specific MoAb; negative reactions are counterstained with
Evans blue. The data are representative of three experiments from
separate infections.
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Although the downregulation of surface CXCR4 by HHV-7 and the
inhibitory effects of SDF-1 on HHV-7 infection are consistent with a
role of CXCR4 as a coreceptor for HHV-7, the final proof of this
hypothesis would be to show that noninfectable cells that are CD4 and
CXCR4 negative are rendered infectable by HHV-7 only when CD4 and CXCR4
are both expressed.
The possibility that CXCR4 might represent an alternative receptor for
HHV-7 in the absence of CD4 was ruled out in infection experiments
performed on the BC7 cells, a derivative line from SupT1 cells that
expresses CXCR4 but not CD4.23 As shown in Fig 4B, BC7
cells were not permissive for HHV-7 infection.
| |
DISCUSSION |
Although CXCR4 functions in association with CD4 to permit the entry of
different HIV isolates,9,10 the precise mechanism of action
of this protein as coreceptor has not yet been fully elucidated.
Irrespective of the mechanism of action of CXCR4 in mediating HIV
entry, it has been clearly established that CXCR4 is downregulated only
by a few HIV-2 isolates, which use CXCR4 as the primary receptor in the
absence of CD4.23 On the other hand, CXCR4 is either
unaffected or minimally downregulated by HIV-1 strains (Fig 2) or by
those HIV-2 strains that still require CD4 for infection and cell
fusion.23
We have shown here that CXCR4 interacts with HHV-7 in a unique manner
compared with HIV. In fact, both CD4 and CXCR4 are downregulated from
the surface of HHV-7-infected CD4+ T cells, although with
different kinetics and probably through different mechanisms. After
HHV-7 infection, CD4 loss is more rapid and involves both
transcriptional and posttranscriptional mechanisms,22
whereas downregulation of surface CXCR4 does not depend on a block of
transcription.
Although initial studies have suggested that chemokine receptor
internalization is not required to block HIV entry, more recent data
indicate that SDF-1 is a more effective inhibitor of T-cell line-adapted HIV isolates on cells expressing endocytosis-competent CXCR4.14,15 This suggests that SDF-1-mediated CXCR4
endocytosis may make a significant contribution to chemokine protection
from HIV entry.
Although the mechanisms of HHV-7-mediated downregulation of CXCR4
remain to be elucidated, the possibility that HHV-7 induced CXCR4
downregulation via an autocrine production of SDF-1 was ruled out,
because SDF-1 mRNA was undetectable by RT-PCR in both HHV-7-infected and uninfected SupT1 cells (data not shown). It is also
particularly remarkable that, whereas SDF-1 induces a rapid but
transient (<1 hour) downregulation of surface CXCR4, HHV-7 infection
produces a persistent loss of surface CXCR4.
Thus, beside the relevance of these finding for HHV-7 pathogenesis, the
identification of the HHV-7 gene product(s) modulating CXCR4 may allow
the design of novel strategies to inactivate CXCR4 by blocking its
surface expression.34
| |
ACKNOWLEDGMENT |
The authors are very grateful to J.A. Hoxie and to G. Campadelli-Fiume
for providing the BC7 cell line and the 5E1 MoAb, respectively.
| |
FOOTNOTES |
Submitted August 18, 1998;
accepted October 1, 1998.
Supported by an University of Maryland School of Medicine Intramural
Research Fund Award, by Telethon Foundation Grant, and by the "AIDS
project" of the Italian Ministry of Health.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Paola Secchiero, PhD, Institute of Human
Virology, University of Maryland, 725 W Lombard St, Baltimore, MD
21201-1192; e-mail: secchier{at}umbi.umd.edu.
| |
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Abstract
Introduction