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IMMUNOBIOLOGY
From the Department of Morphology and Embryology, Human
Anatomy Section, University of Ferrara; the Department of
Biomorphology, G. D'Annunzio University of Chieti; the Institute of
Human Anatomy, University of Parma, Italy; and the Institute of Human
Virology, University of Maryland Biotechnology Institute, Baltimore.
Human herpesvirus 7 (HHV-7) is endemic in the adult human
population. Although HHV-7 preferentially infects activated
CD4+ T lymphocytes, the consequence of T-cell infection for
viral pathogenesis and immunity are still largely unknown. HHV-7
infection induces apoptosis mostly in uninfected bystander cells but
not in productively infected CD4+ T cells. To dissect the
underlying molecular events, the role of death-inducing ligands
belonging to the tumor necrosis factor (TNF) cytokine superfamily was
investigated. HHV-7 selectively up-regulated the expression of
TNF-related apoptosis-inducing ligand (TRAIL), but not that of CD95
ligand or TNF- Human herpesvirus 7 (HHV-7) is a CD4+ T
lymphotropic herpesvirus isolated for the first time in 1990; it
belongs to the Betaherpesvirinae subfamily.1 The overall
structure of the HHV-7 genome is identical to that of HHV-6, with a
long, unique component of approximately 133-kb pairs flanked by a
single direct repeat (DR) unit at each end.2-4 HHV-7 is a
prevalent virus toward which most (more than 90%) of the population is
seropositive by adulthood.5,6 Although the portal of entry
of HHV-7 into the human host, the sites of primary infection, and the
sites of latency have yet to be fully elucidated, it has been
demonstrated that the human salivary system is a source for persistent
production of infectious HHV-7.7 Moreover, it has been
previously shown that the CD4 antigen, expressed at high levels on the
surfaces of a subset of mature T cells, is the high-affinity receptor
for HHV-7.8,9
Primary HHV-7 infection has been associated with rash, exanthema
subitum, chronic fatigue syndrome, chronic Epstein-Barr-like syndrome,
liver dysfunction, and central nervous system
manifestations.10-12 More important, because HHV-7 is
widespread in the adult population,5,6 it represents a
potential opportunistic agent in immunocompromised hosts such as
patients undergoing bone marrow or organ
transplantation.13-18 In this respect, HHV-7 DNA has been
found in up to 50% of bone marrow samples obtained from healthy
donors,14 and we have recently shown that it can infect
CD34+ hematopoietic progenitors.19 Moreover,
it has been demonstrated that reactivation of HHV-7 occurs after
renal,16,17 liver,18 and bone
marrow15,20 transplantation, and it has been shown that
HHV-7 seroconversion represents a risk factor for cytomegalovirus disease in transplant recipients independently of donor-recipient cytomegalovirus serostatus.17,18 At the cellular level, it is conceivable that once reactivated, HHV-7 worsens the state of
immunodeficiency because of its selective tropism for CD4+
T lymphocytes,8,9,13 whose infection results in
cytotoxicity 8,21-23 and immunomodulatory
activities.9,24-26
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand
(TRAIL/Apo2 ligand) is a recently described death-inducing ligand (DIL)
belonging to the TNF superfamily that shows structural and functional
similarities with CD95 (Apo1/Fas) ligand (L), including the use of
Fas-associated death domain as an adaptor molecule.27,28 Like other members of the TNF family, TRAIL is a type 2 membrane protein with an intracellular amino-terminal portion, an internal trans-membrane domain, and a carboxyl terminus external to the cell. In
addition, a soluble form of TRAIL has been described,29 as
also previously shown for TNF- The aim of this study was to investigate the functional expression of
DIL and DIL receptors and, in particular, of TRAIL and its receptors
during HHV-7 infection. For this purpose, we have used, as targets for
HHV-7 infection, the SupT1 lymphoblastoid CD4+ T-cell line
and primary CD4+ T lymphocytes, purified from the
peripheral blood of healthy subjects.
Cells
Viral infections
Western blot analysis For the analysis of TRAIL protein expression, Western blot analysis was performed on approximately 5 to 10 × 106 cells/experimental point. Cells were harvested in lysis buffer containing 1% Triton X-100, sonicated, and processed for Western blot. Protein determination was performed by Bradford assay (Bio-Rad, Richmond, CA). Equal amounts of proteins for each sample were migrated in 12% polyacrylamide gel electrophoresis and blotted onto nitrocellulose filters. Blotted filters were blocked for 60 minutes in a 3% suspension of dried skim milk in phosphate-buffered saline (PBS) and were incubated overnight at 4°C with a 1:200 dilution of anti-TRAIL mAb (clone B35-1; Pharmingen, San Diego, CA). Filters were washed and further incubated for 1 hour at room temperature with a 1:1000 dilution of peroxidase-conjugated anti-mouse immunoglobulin G (Sigma). Specific reactions were revealed with the enhanced chemiluminescence Western blotting detection reagent (Amersham, Arlington Heights, IL). Densitometric analysis of immunoreactive bands was performed with an imaging densitometer (model GS 670; Bio-Rad Italia, Milan, Italy), using the Molecular Analyst software. Results were reported as arbitrary units and as percentage expression in HHV-7-infected samples compared with uninfected ones.Flow cytometric analysis Aliquots of 1 × 106 cells/experimental point were subjected to single- or multiple-label staining to examine the presence of surface antigens, as described previously.9 Surface TRAIL expression was analyzed by indirect staining using 1 µg RIK-2 anti-TRAIL mA (a generous gift from Dr Hideo Yagita, Juntendo University School of Medicine, Tokyo, Japan), followed by phycoerythrin (PE)-labeled goat anti-mouse IgG (Sigma). Expression of TRAIL-receptor (R)1, TRAIL-R2, TRAIL-R3, and TRAIL-R4 was analyzed by indirect staining using goat anti-human TRAIL-R1, TRAIL-R2, TRAIL-R3, and TRAIL-R4 antibodies (all from R&D System, Oxon, United Kingdom) followed by PE-conjugated rabbit anti-goat IgG (Sigma). Aspecific fluorescence was assessed by using either normal mouse IgG (for TRAIL) or normal goat IgG (for TRAIL receptors) followed by a second layer as above. CD4 expression was analyzed by using the Cy5-PE-conjugated mAb (Becton Dickinson, San Jose, CA). Analysis was performed by using a FACScan flow cytometer (Becton Dickinson) and the Lysis II software (Becton Dickinson). Data collected from 10 000 cells are reported as either percentage positive cells or mean fluorescence intensity (MFI) values.JAM test The JAM assay36 was performed to measure the degree of cell death induced by HHV-7. For this purpose, target cells were labeled with [3H] thymidine (TdR). When cell death occurred in the labeled cell population, DNA fragments were washed through glass fiber filters during cell harvesting. In contrast, DNA from surviving target cells remained intact and was captured by the filters. Percentage cell death was calculated by comparing the amount of [3H]TdR bound to filters in the presence and absence of the apoptosis-inducing events. Briefly, proliferating uninfected SupT1 or primary CD4+ or CD8+ T cells (target) were pulsed overnight with .37 MBq/mL (10 µCi/mL) [3H]TdR (New England Nuclear, Boston, MA), washed with complete medium 3 times, and plated into wells that contained graded numbers of HHV-7-infected (effector) cells or equivalent numbers of uninfected cells as control. After incubation at 37°C, cells were harvested onto glass fiber filters by using vacuum aspiration, and radioactivity was counted. All measurements given represent the mean of 6 wells. When required, blocking antibodies were added to HHV-7-infected effector cells 1 hour before incubation with uninfected (target) cells. Anti-TRAIL neutralizing polyclonal Ab (R&D Systems) was used at 1 µg/mL; anti-TNF- neutralizing polyclonal Ab (R&D
Systems) was used at 1 µg/mL; anti-CD95 Fab' mAb (kindly provided by
Dr Peter Krammer, University of Heidelberg, Germany), which
specifically blocks the ability of CD95L to interact with CD95, was
used at 0.1 µg/mL. In preliminary titration experiments, the
neutralizing activity of 0.01 to 10 µg/mL anti-TNF- and anti-CD95
Fab' mAb was tested, and we have used those concentrations of
antibodies, which were able to completely inhibit the cell death
induced by 10 ng recombinant TNF- and of anti-CD95 IgM agonistic
antibody, respectively. Results are expressed as percentage DNA
fragmentation or DNA loss.
Recombinant TRAIL Both rHis6-tagged TRAIL and rHis6-tag control peptides were produced in bacteria and were purified by affinity chromatography on Ni2+ affinity resin, as previously described.37 In preliminary dose- and time-course experiments performed in SupT1 cells, TRAIL-induced apoptosis was complete by 20 hours and reached a plateau at the concentration of 1 µg/mL. In contrast, equimolar concentrations of rHis6-tag control peptide did not show any significant toxicity. Therefore, a 20-hour incubation period and a concentration of 1 µg/mL TRAIL were chosen for experiments in uninfected and HHV-7-infected SupT1 cells.Evaluation of apoptosis The presence of apoptosis was examined by flow cytometry after propidium iodide (PI) staining and by fluorescence microscopy after 4',6-diamidine-2'-phenylindole dihydrochloride (DAPI) staining. For flow cytometry studies, cells were harvested by centrifugation at 200g for 10 minutes at 4°C, fixed with cold 70% ethanol for at least 1 hour at 4°C, and treated as previously described.21,38 Samples were then pelleted, treated with 0.5 µg RNAse (type I-A; Sigma), and resuspended in PBS containing 50 µg/mL PI. Analysis was performed by FACScan with the FL2 detector in logarithmic mode using Lysis II software (Becton Dickinson). Data were expressed as percentage of apoptotic versus nonapoptotic cells belonging to all cell cycle phases. It should be emphasized that the percentage of apoptosis was calculated using very strict criteria, which have been previously described,38 to score only apoptotic cells and excluding all cell debris.For DAPI staining of nuclei, cells were washed with PBS, fixed in paraformaldehyde 4% for 10 minutes, permeabilized in Triton X100 0.1% for 10 minutes, washed again with PBS, and incubated with 500 ng/mL DAPI (Sigma) in PBS for 15 minutes at 37°C in a dark, humidified chamber. After several washes in PBS, the coverslips were mounted on PBS-glycerin, and the intercalation of DAPI was visualized by means of an Axiophot Zeiss fluorescence microscope (Carl Zeiss, Thornwood, NY). Statistics Statistical analysis was performed using the 2-tailed Student t test.
HHV-7 infection up-regulates TRAIL protein expression CD4+ T lymphoblastoid SupT1 cells, which show a high susceptibility to HHV-7 infection,8,21-23 were either mock-treated or infected with HHV-7 at a multiplicity of infection of 0.1. The peak of infection was usually observed at day 8 after infection, when most cells were infected with HHV-7, as evaluated by the progressive increase of balloonlike polyploid cells and by specific indirect immunofluorescence for HHV-7 antigens (52.6% ± 9% positive cells; mean ± SD of 5 separate experiments) (Figure 1A). Semiquantitative evaluation of total TRAIL protein expression was performed by Western blot analysis of the protein cell lysates after blotting with a specific anti-TRAIL mAb, and with an anti- -actin
mAb as a control for protein loading (Figure 1B). A 33- to 35-kd
protein corresponding to the full-length monomeric TRAIL was already
expressed in uninfected SupT1 cells and was up-regulated after HHV-7
infection (Figure 1B). The amount of TRAIL protein, as evaluated by
densitometric analysis of the bands, was significantly
(P < .01) increased in HHV-7-infected versus
uninfected cultures (percentage increase was 390% ± 45% of 5 separate experiments).
Because TRAIL is a type 2 membrane protein,27 the surface
expression of TRAIL was next investigated by flow cytometry. SupT1 cells were either mock-treated or were infected with HHV-7 and cultured
for 8 days, when the cells were labeled with an anti-TRAIL mAb.
Although surface TRAIL was not detectable in SupT1 control cells, a dim
but clearly detectable expression of surface TRAIL was observed in
HHV-7-infected SupT1 cells (Figure 2A).
These findings are consistent with the data of other authors, who
demonstrated that TRAIL protein is expressed as a constitutive
intra-cytoplasmic protein in lymphoid CD4+ T
cells.39,40 Although small, the difference in TRAIL
surface expression between HHV-7-infected (MFI, 7.8 ± 1.6) and
uninfected (MFI, 5 ± 1.3, corresponding to the background level)
cells was reproducible in various experiments (mean ± SD of 5 separate experiments; P < .05). Moreover, the
up-regulation of surface TRAIL mediated by HHV-7 was specific; the
surface expression of other DIL, such as CD95L and TNF-
TRAIL is a mediator of HHV-7-induced cytotoxicity To evaluate whether the up-regulation of TRAIL by HHV-7 was functional, a JAM cytotoxicity assay was performed.36 [3H]TdR-labeled SupT1 (target) cells were incubated with increasing amounts of HHV-7-infected or mock-infected cells (effector cells) for 16 hours. HHV-7-infected cells induced marked and specific target cell lysis, as determined by calculating DNA loss,36 that was dose dependent (Figure 3A). On the other hand, mock-infected cells and the supernatant of the HHV-7-infected cultures did not induce any significant target cell lysis (Figure 3A). This first group of experiments indicated that HHV-7-induced cell death in SupT1 cells required cell-to-cell contact. Then, to determine whether HHV-7-induced cell death was mediated by TRAIL, uninfected labeled SupT1 cells were incubated with HHV-7-infected cells (target-effector ratio, 1:4) for 16 hours in the absence or presence of anti-TRAIL neutralizing polyclonal Ab. The presence of anti-TRAIL Ab significantly (P < .01) inhibited cell lysis induced by HHV-7-infected SupT1 cells (Figure 3B). Conversely, both anti-CD95 Fab' and anti-TNF- neutralizing
antibodies had modest effects on the cytotoxic activity induced by
contact with HHV-7-infected cultures (Figure 3B).
Parallel experiments were carried out using primary CD4+ T
lymphocytes, preactivated with phytohemagglutinin plus IL-2 for 3 days,
and then were infected with HHV-7 and cultured in the presence of 5 U/mL IL-2 for an additional 13 days (peak of infection). As expected on
the basis of previous studies,8,21-23 the kinetics of
infection in CD4+ T cells was slower with respect to that
observed in SupT1 lymphoblastoid T cells. However, at day 13 after
infection, several cells were infected by HHV-7 (34% ± 11%;
mean ± SD of 5 separate experiments), as evaluated by indirect
immunofluorescence analysis of HHV-7 antigens (Figure
4A). The amount of TRAIL was
significantly (P < .01) higher in HHV-7-infected
CD4+ T lymphocytes than in uninfected control cells (Figure
4B), starting from day 10 after infection (256% ± 55% of increase
at day 13 after infection; mean ± SD of 5 separate experiments).
Remarkably, when using primary cells, HHV-7-infected cultures induced
specific target cell lysis after incubation with labeled uninfected
primary CD4+ T cells that was significantly
(P < .01) and selectively inhibited by the presence of
anti-TRAIL neutralizing Ab (Figure 4C). In some experiments, primary
HHV-7-infected CD4+ T cells were cocultured with labeled
uninfected CD8+ T cells purified from the same donor.
HHV-7-infected CD4+ T cells efficiently killed uninfected
CD8+ T cells, but apparently in a DIL-independent manner,
as indicated by the failure of anti-TRAIL, anti-CD95 Fab', and
anti-TNF-
HHV-7 infection selectively down-modulates TRAIL-R1 expression The surface expression of TRAIL receptors was next evaluated at various time points after infection by flow cytometry (Figure 5A). Uninfected SupT1 cells showed high levels of surface expression of both TRAIL-R1 and TRAIL-R2, whereas TRAIL-R3 and TRAIL-R4 were not detectable. In HHV-7-infected SupT1 cultures, the expression of surface TRAIL-R1, but not TRAIL-R2, showed a progressive and significant (P < .01) decrease in comparison to uninfected controls (Figure 5A). On the other hand, TRAIL-R3 and TRAIL-R4 surface antigens were unaffected by HHV-7 infection (Figure 5A). The specificity of HHV-7-mediated TRAIL-R1 down-regulation was further confirmed by the analysis of other receptors of the TNF receptor superfamily (CD95, TNF-R1, and TNF-R2), whose expression was unchanged on HHV-7 infection (Figure 5B).
In consideration of the promiscuity of infected and uninfected cells in
HHV-7-infected cultures, we next sought to elucidate whether TRAIL-R1
down-regulation occurred in infected or uninfected cells. In this
respect, we have previously shown that HHV-7 infection of
CD4+ T lymphocytes induces a progressive down-regulation of
surface CD4, which represents the high-affinity receptor for HHV-7, and that the expression of HHV-7 antigens correlates with the loss of
surface CD4 receptor.9 Therefore, double staining was next performed with anti-TRAIL-R1 plus anti-CD4 mAbs (Figure
6A). At flow cytometry analysis of
control uninfected SupT1 cells, as expected, all the cells coexpressed
TRAIL-R1 and CD4, whereas in the HHV-7-infected cultures, 2 distinct
cell populations (TRAIL-R1+/CD4+ and
TRAIL-R1
In additional experiments, we investigated whether the HHV-7-mediated
down-modulation of TRAIL-R1 protects the
HHV-7-infected/CD4 The occurrence of apoptosis was next investigated by PI staining
and flow cytometry analysis (Figure 7A).
As expected on the basis of our previous studies,21,26
HHV-7-infected cultures showed a significant (P < .01)
percentage of apoptotic cells (12% ± 4%; mean ± SD of 4 separate experiments) with respect to uninfected SupT1 cultures, which
only displayed background levels of apoptosis (2% ± 1.5%,
mean ± SD of 4 separate experiments). On the other hand, the
addition of rTRAIL induced a marked (P < .01) increase in
the percentage of apoptosis in uninfected cells (29% ± 7%; mean ± SD of 4 separate experiments) and a much lower increase in
HHV-7-infected cells (22% ± 5%; mean ± SD of 4 separate
experiments) (Figure 7A). PI staining and flow cytometry analysis do
not allow discrimination between HHV-7-infected and uninfected cells,
which coexist in HHV-7- infected cultures. Therefore, the occurrence of TRAIL-induced apoptosis was next analyzed in combination with the
expression of viral antigens by using dual-label staining for cell
nuclei (DAPI) and HHV-7 antigens (Figure 7B; Table
1). After 20 hours of TRAIL challenge,
the presence of apoptotic nuclei, evaluated by DAPI staining, was
clearly detected in uninfected SupT1 cell cultures at fluorescence
microscopy analysis (Table 1). In HHV-7-infected cultures, on TRAIL
challenge, few cells staining positively for the expression of viral
antigens exhibited an apoptotic morphology, resulting in a
significantly (P < .01) lower number compared with
apoptotic cells among the HHV-7 antigen-negative cells (Table 1).
These findings clearly suggest that the cells expressing HHV-7 antigens
are protected from TRAIL-induced apoptosis.
The presence of at least 5 TRAIL receptors indicates that TRAIL is involved in multiple processes, but the precise roles of TRAIL in health and disease are still largely unknown. Although TRAIL and TRAIL receptors are expressed in various tissues,27,41,42 TRAIL does not induce apoptosis of most nontransformed cells.41,42 It has been shown that TRAIL is up-regulated on T-cell activation,29,39,40 and one of the functions of TRAIL in vivo is to maintain immune homeostasis by inhibiting the cell cycle progression of T lymphocytes.43 We have here demonstrated for the first time that HHV-7 infection
induces the simultaneous up-regulation of TRAIL and down-regulation of
TRAIL-R1 on the surfaces of CD4+ T cells. Among the
different DIL (TRAIL, CD95L, TNF- Many viruses have their own antiapoptotic genes or are able to up-regulate antiapoptotic cellular genes, which can block premature death of infected cells.45 As do other large DNA-containing herpesviruses, HHV-7 probably uses multiple viral defense mechanisms that cooperate to prevent premature death of the host infected cell. Our findings strongly suggest that one of these mechanisms is the up-regulation of surface TRAIL, which efficiently kills uninfected T lymphocytes, coupled to the down-regulation of TRAIL-R1 in the productively HHV-7-infected cells. Because HHV-7 is dependent on CD4+ T cells for the production of mature virions, these biologic effects may represent part of a strategy to facilitate a persistent infection or to prolong the survival of the infected cells to maximize the production of viral progeny. Of note, this represents a unique feature of HHV-7 with respect to other herpesviruses. In fact, it has been shown that cytomegalovirus induces the up-regulation of TRAIL-R1 and TRAIL-R2 in infected fibroblasts, which are therefore more susceptible to TRAIL-mediated cytotoxicity,46 whereas HSV-1 selectively up-regulates CD95L but not TRAIL in infected lymphocytes.47 Although the pathogenicity of HHV-7 remains largely to be determined mainly because of the relatively recent discovery of this herpesvirus, compelling evidence indicates that latent HHV-7 infection is reactivated in immunocompromised patients, such as transplant recipients.10,13-16,18-20 Moreover, it has been shown that the expression of HHV-7 is significantly increased in peripheral lymphoid tissues of patients with acquired immune deficiency syndrome,48 strongly indicating that HHV-7 acts as an opportunistic agent in these patients. In this respect, other authors have shown that the TRAIL system is up-regulated during human immunodeficiency virus-1 infection and likely contributes to the pathogenesis of human immunodeficiency virus-1 disease.49-51 Our data demonstrate that the TRAIL-mediated induction of T-cell death may represent an important immune evasion mechanism of HHV-7, helping the virus to persist in the host organism throughout its lifetime. The functional up-regulation of TRAIL may also contribute to the role of HHV-7 as an opportunistic agent in transplantation patients and in patients with acquired immune deficiency syndrome.18-20,51
Submitted February 12, 2001; accepted June 8, 2001.
Supported by AIDS grant and local funds of the Universities of Ferrara and Chieti; A.G. is supported by an FIRC fellowship.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Giorgio Zauli, Department of Biomorphology, G. D'Annunzio University of Chieti, Via dei Vestini 6, 66100 Chieti Scalo (CH), Italy; e-mail: g.zauli{at}morpho.unich.it.
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© 2001 by The American Society of Hematology.
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  E. K. Rowinsky Targeted Induction of Apoptosis in Cancer Management: The Emerging Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Receptor Activating Agents J. Clin. Oncol., December 20, 2005; 23(36): 9394 - 9407. [Abstract] [Full Text] [PDF]
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 E. Ishikawa, M. Nakazawa, M. Yoshinari, and M. Minami Role of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in Immune Response to Influenza Virus Infection in Mice J. Virol., June 15, 2005; 79(12): 7658 - 7663. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
/CD4
mediates a novel antiviral activity through dynamic modulation of TRAIL and TRAIL receptor expression.
J Immunol.
1999;163:920-926