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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 956-967
 -Interferon Produced by CD8+ T Cells Infiltrating
Kaposi's Sarcoma Induces Spindle Cells With Angiogenic Phenotype and
Synergy With Human Immunodeficiency Virus-1 Tat Protein: An Immune
Response to Human Herpesvirus-8 Infection?
By
Valeria Fiorelli,
Rita Gendelman,
Maria Caterina Sirianni,
Hsiao-Kuey Chang,
Sandra Colombini,
Phillip D. Markham,
Paolo Monini,
Joseph Sonnabend,
Aldo Pintus,
Robert C. Gallo, and
Barbara Ensoli
From the Department of Allergy and Clinical Immunology, University of
Rome "La Sapienza," Rome, Italy; the Laboratory of Tumor Cell
Biology, National Cancer Institute, National Institutes of Health,
Bethesda, MD; the Institute of Human Virology, University of Maryland
at Baltimore, Baltimore, MD; Advanced BioScience Laboratories, Inc,
Kensington, MD; Laboratory of Virology, Istituto Superiore di Sanita',
Rome, Italy; Community Research Initiative on AIDS New
York; Istituto Di Clinica Medica, Cattedra Di Genetica,
Cagliari, Italy.
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ABSTRACT |
Kaposi's sarcoma (KS) is an angioproliferative disease associated
with infection by the human herpesvirus-8 (HHV-8). HHV-8 possesses
genes including homologs of interleukin-8 (IL-8) receptor, Bcl-2, and
cyclin D, which can potentially transform the host cell. However, the
expression of these genes in KS tissues is very low or undetectable and
HHV-8 does not seem to transform human cells in vitro. In addition, KS
may not be a true cancer at least in the early stage. This indicated
that besides its transforming potential, HHV-8 may act in KS
pathogenesis also through indirect mechanisms. Evidence suggests that
KS may start as an inflammatory-angiogenic lesion mediated by
cytokines. However, little is known on the nature of the inflammatory
cell infiltration present in KS, on the type of cytokines produced and
on their role in KS, and whether this correlates with the presence of
HHV-8. Here we show that both acquired immunodeficiency syndrome
(AIDS)-KS and classical KS (C-KS) lesions are infiltrated by
CD8+ T cells and CD14+/CD68+
monocytes-macrophages producing high levels of  -interferon (IFN) which, in turn, promotes the formation of KS spindle cells with angiogenic phenotype. IFN, in fact, induces endothelial cells to
acquire the same features of KS cells, including the spindle morphology
and the pattern of cell marker expression. In addition, endothelial
cells activated by IFN induce angiogenic lesions in nude mice
closely resembling early KS. These KS-like lesions are accompanied by
production of basic fibroblast growth factor, an angiogenic factor
highly expressed in primary lesions that mediates angiogenesis and
spindle cell growth. The formation of KS-like lesions is upregulated by
the human immunodeficiency virus Tat protein demonstrating its role as
a progression factor in AIDS-KS. Finally, IFN and HLA-DR expression
correlate with the presence of HHV-8 in lesional and uninvolved tissues
from the same patients. As HHV-8 infects both mononuclear cells
infiltrating KS lesions and KS spindle cells, these results suggest
that HHV-8 may elicit or participate in a local immune response
characterized by infiltration of CD8+ T cells and intense
production of IFN which, in turn, plays a key role in KS
development.
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INTRODUCTION |
KAPOSI'S SARCOMA (KS) is a proliferative
disease of vascular origin particularly frequent and aggressive in
human immunodeficiency virus (HIV-1)-infected homosexual men (acquired
immunodeficiency syndrome [AIDS]-KS) as compared with classical KS
(C-KS) that is rare and indolent.1-3 However, these forms
have the same histopathology. In the very early stages, KS is
characterized by inflammatory cell infiltration, endothelial cell
activation, and angiogenesis. This is followed by the appearance of the
typical spindle-shaped cells that represent a heterogeneous population
dominated by activated endothelial cells mixed with macrophages and
dendritic cells.4-7 In advancing lesions, spindle cells
tend to become the predominant cell type, although angiogenesis remains
always a prominent feature.
A new herpesvirus, termed KS-associated herpesvirus (KSHV) or human
herpesvirus-8 (HHV-8), has been recently identified in KS
tissues.8 In contrast with other viruses, HHV-8 has been consistently detected in all forms of KS,9-13 in peripheral
blood mononuclear cells (PBMC) from the same patients, and, at a lower frequency, in AIDS patients without KS and in normal individuals, particularly in geographical areas at high risk for KS14-17
(and G. Rezza et al, submitted). Other studies showed that
HHV-8 infection can be predictive of KS development.18-20
Thus, evidence suggests that HHV-8 may have an important role in KS
pathogenesis.
HHV-8 possesses several genes acquired from the host, including
homologs of macrophage inflammatory protein (MIP) (v-MIP-I and
v-MIP-II), interleukin-6 (IL-6) (v-IL-6), IL-8 receptor (v-IL-8R), Bcl-2 (v-Bcl-2), and cyclin D (v-cyclin D).21-29 Most of
these genes have been shown to be functional and v-IL-8R has in vitro transforming activity.21,23-26,29 This suggested that they
may participate in KS cell transformation or in the induction of basic fibroblast growth factor (bFGF),23 an angiogenic factor
that has a key role in KS pathogenesis.30-32 However, to
exert a role in KS cell transformation, these viral genes should be
expressed in the transformed cells as found in primary effusion
lymphomas (PEL) and PEL-derived cell lines.21-23 In
contrast, the expression of these viral genes in KS tissues is low or
undetectable,21-23,26,28,33 whereas the human bcl-2 and
IL-6 are expressed at very high levels in primary
lesions.34,35 In addition, the only two tumor cell lines
derived from KS do not contain HHV-8,36 and spindle cells derived from the lesions are latently infected, but they lose the virus
on culture37-39 (and our unpublished data). Finally, HHV-8
does not seem to transform human endothelial cells, the precursors of
KS spindle cells, or B cells in vitro.40
Recent findings show that, in addition to primary B
cells,41 HHV-8 is present in circulating
monocytes42 (and S. Colombini et al,
submitted), in spindle-like macrophagic cell progenitors of the blood of KS patients43,44 and in infiltrating
mononuclear cells of KS lesions including monocytes and macrophages
where the virus yields a productive infection.42,45,46
Altogether these observations suggest that HHV-8 may act through
different mechanisms in KS pathogenesis.
Previous studies by us and others showed that KS behaves as a
cytokine-mediated disease, and that, at least in early stages, KS is
not a true cancer, but a hyperplastic-proliferative
disease.47-49 bFGF and vascular endothelial cell growth
factor (VEGF) are highly expressed in spindle cells of both AIDS-KS and
C-KS, and they mediate the spindle cell growth, angiogenesis, and edema
of KS30-32,50,51 (and F. Samaniego et al,
submitted). Other data showed that the extracellular HIV-1
Tat protein released by infected cells can increase synergistically the
angiogenensis and spindle cell growth mediated by
bFGF.33,52-56 As extracellular Tat is present in AIDS-KS lesions and its receptors are highly expressed by vessels and spindle
cells,32,57 this suggested that Tat may increase the frequency and aggressiveness of KS in infected individuals acting as a
progression factor.
Further data suggested that inflammatory cytokines (IC) may trigger
these events. Conditioned media (CM) from activated T cells (TCM)
induce the production and release of bFGF and VEGF in cultured KS
and/or endothelial cells58,59 (and F. Samaniego et
al, submitted). In addition, TCM-treated endothelial cells acquire features similar or identical to KS cells and, as observed with
AIDS-KS cells, they become responsive to the growth, invasion, and
adhesion effects of Tat.54-57 TCM contain a variety of IC
including tumor necrosis factor (TNF), IL-1, IL-6, oncostatin M (OM),
and -interferon (IFN) (see Materials and Methods
section),53-59 and some of them (TNF , IL-6, IL-1, OM)
have been found in KS,60-62 suggesting a role for the
immune system and in particular of host IC in the induction and
progression of KS. In particular, the presence of HHV-8 productively
infected cells in KS tissues suggests that the virus may trigger an
inflammatory response and the expression of cytokines. However, little
or nothing is known on the type of inflammatory cell infiltration,
specific cytokine production, and role of these cytokines in KS
pathogenesis or whether the presence of these cytokines correlates with
that of HHV-8. Here we show that (1) KS lesions from both AIDS-KS and
C-KS contain a prevalent CD8 T-cell infiltration and infiltration with
monocytes-macrophages; (2) these cells produce IC and in particular
IFN; (3) IFN is required to induce endothelial cells to acquire
the phenotypic and functional features of KS spindle cells, both in
vitro and in vivo, and to induce angiogenic KS-like lesions in nude
mice whose frequency and intensity is increased by the HIV-1 Tat
protein; and (4) IFN and HLA-DR expression in tissues is associated
with the presence of HHV-8.
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MATERIALS AND METHODS |
Immunostaining of tissues and cells.
Frozen sections from KS and uninvolved tissues were fixed in cold
acetone and single- or doubly-stained by the alkaline phosphatase antialkaline phosphatase (APAAP) method alone or combined with the
peroxidase antiperoxidase (PAP) method. For APAAP single method, monoclonal antibodies (MoAbs) were used directed against IFN (1:25,
Genzyme Diagnostics, Cambridge, MA), TNF (1:200), IL-1 (1:200),
HLA-DR (1:20), CD4 (1:20), CD8 (1:100), CD14 (1:100), CD68 (1:200),
CD20 (1:200) (all from DAKO, Golstrup, Denmark). For double-staining
experiments, the APAAP and the PAP methods were used by combining the
antibodies described above with a rabbit polyclonal antibody directed
against IFN (1:200, Genzyme) as described previously.32
All incubations were performed at room temperature. Briefly, for
single-staining, the slides were incubated with the MoAb for 30 minutes. After washing with Tris-buffered solution (TBS), the rabbit
antimouse IgG (1:25; Dako) was applied for 20 minutes and after
additional washing with TBS, the slides were incubated with APAAP
(mouse) complex (1:25; Dako) for 20 minutes. The second and the third
steps were repeated to amplify the reactions. The reaction was
developed with the Fast Red Substrate System (Dako) and slides
counterstained with Mayer's hematoxylin solution (Sigma Chemical Co,
St Louis, MO). For double-staining (APAAP/PAP)32 the
endogenous peroxidase activity was suppressed by using Peroxidase
Blocking Reagent (Dako) for 5 minutes. To reduce the background, slides
were incubated with normal swine serum (1:5, Dako) for 20 minutes,
followed by the addition of MoAbs. After 30 minutes of incubation and
washing in TBS, the rabbit polyclonal antibody was added for 30 minutes. After washing in TBS, the slides were incubated with goat
antimouse (1:25; Dako) for 30 minutes, rinsed again, and swine
antirabbit (1:100; Dako) was applied for an additional 30 minutes. The
slides were washed again and APAAP (mouse) complex was applied for 30 minutes, rinsed, and then PAP (rabbit) (1:400; Sigma) was applied for
30 minutes. The APAAP reaction was developed in Fast Red Substrate
System (Dako) for 20 minutes and the PAP reaction was developed with 3'3 diaminobenzidin (DAB) solution for 5 minutes. The slides were counterstained as described above. The percentage of red (APAAP) or
yellow-brown (PAP) positive cells alone or combined were counted separately in duplicate samples for each experiment and in five high
power microscopic fields (HPMF) per slide.
bFGF staining was performed on frozen tissue sections from the sites of
inoculation of mice injected with untreated, TCM-treated, or
IFN-treated human umbilical vein endothelial (HUVE) cells by using a
rabbit polyclonal anti-bFGF antibody (Santa Cruz Biotechnology Inc,
Santa Cruz, CA) diluted 1:20 or 1:40 in 1% phosphate-buffered saline-bovine serum albumine (PBS-BSA) and the PAP method as described above, but by using the peroxidase-antiperoxidase from Dako (1:100 dilution) as described previously.31,59
The staining of HUVE cells for CD34, vascular endothelial
(VE)-cadherin, FVIII-RA, EN-4, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecular-1 (ICAM-1), endothelial leukocyte adhesion molecule (ELAM), and HLA-DR was performed by the
APAAP method with cytospin preparations or cells grown on gelatine-coated slides. Slides were fixed in cold acetone for 10 minutes, air dried, and then stained as described for tissue staining.
The primary antibodies were applied for 20 minutes. The percentage of
positive cells in duplicate samples for each experiment and in five
HPMF per slide was then evaluated. The specificity and derivation of
the primary antibodies used in these experiments are shown in
Table 1.
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Table 1.
Cell Marker Expression in HUVE Cells Before or After
Treatment With TCM, RTCM Lacking or Containing IFN, or IFN
Alone
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PCR and Southern blot analysis or liquid hybridization.
High molecular weight DNA was extracted from frozen tissues using a
standard phenol/chloroform procedure. Polymerase chain reaction (PCR)
analysis was performed with the following sets of primers. Two sets of
primers derived from the published sequence8 were used to
amplify HHV-8 sequences. Set 1: (700-810) 5 TAG CCG AAA GGA TTC
CAC CAT 3, and (1207-1228) 5 GGA TCC GTG TTG TCT ACG TC
3; Set 2: (112-130) 5 TGC GAT CTG TTA GTC CGGA 3, and (430-453) 5 ATT CGC CAA GGA CGT ACA GCA 3. The probe
was a 45mer (nucleotides 980-1025 of the published sequences) for primers set 1, and a 51mer (nucleotides 181-232 of the published sequence) for primers set 2, respectively. Primers used for
Epstein-Barr virus (EBV) amplification were: 5 AGG
CTG CCC ACC CTG AGG AT 3, and 5 GCC ACC TGG CAG CCC TAA
AG 3 and the probe was the internal oligonucleotide 5 GTT
GCC GCC AGG TGG CAGC 3. Primers used for HHV-6 amplification
were: 5 GCG TTT TCA GTG TGT AGT TCG GCA G 3 and 5
TGG CCG CAT TCG TAC AGA TAC GGA GG 3, and the probe was 5
GCT AGA ACG TAT TTG CTG CAG AAC G 3. Primers used for HHV-7
amplification were (1-26): 5TAT CCC AGC TGT TTT CAT ATA GTA AC
3 and (186-161) 5 GCC TTG CGG TAG CAC TAG ATT TTT TG
3, and the probe was (82-111) 5 CCT AAT GAA GGC TAC TTT GAA GTA CAA ATG 3. Primers used for cytomegalovirus
(CMV) were: (2038-2057) 5 GGT GCT CAC GCA CAT TGA
TC 3 and (2300-2281) 5 AGA CCT TCA TGC AGA TCT CC
3 and the probe was (2133-2162) 5 TGA TGA CCA TGT ACG GGG
GCA TCT CTC TCT 3. Primers used for -globin were (54-73)
5 CAA CTT CAT CCA CGT TCA CC 3 and (-195 through -176)
5 GAA GAG CCA AGG ACA GGT AC 3. PCR was performed under standard buffer conditions (1 mmol/L MgCl2) using the ampliTAQ PCR
amplification kit (Perkin-Elmer-Cetus, Norwalk, CT) according to the
manufacturer's instructions. After an initial denaturation of 5 minutes at 94°C, 35 cycles of denaturation (92°C for 1 minute), annealing (55°C for 2 minutes) and extension (72°C for 2 minutes) were performed on a DNA thermal cycler 480 (Perkin-Elmer-Cetus). All PCRs were subjected to a final extension of 7 minutes at 72°C. PCR products were analyzed by agarose gel
fractionation and Southern blot hybridization or by liquid
hybridization using internal oligonucleotides as
32P-end-labeled probes. For liquid hybridization, 10 µL
of amplified DNA was mixed with 1 µL of 32P-labeled
oligonucleotide and 5 µL of OH1.1 buffer (66.7 mmol/L NaCl and 44 mmol/L EDTA). The sample was then overlaid with mineral oil and
subjected to 5 minutes of denaturation at 94°C and 15 minutes
annealing at 55°C in a Perkin Elmer Thermal Cycler 480. The product
was then loaded in a 10% TB acrylamide minigel (Novex, San Diego, CA)
and exposed with Kodak XOMAT film for 1 hour to 12 hours. All cases
negative by Southern blot analysis were tested again by liquid
hybridization.
Preparation of TCM and reconstituted TCM (RTCM).
TCM were prepared from human T-lymphotropic virus type
II-infected/transformed (nonvirus-producing) CD4+ T cells
as previously described.53-55 These CM contain the same cytokines produced by mitogen-activated PBL or enriched T cells from
normal donors and do not contain viral proteins.53 The average concentration of these cytokines as determined by enzyme-linked immunosorbent assay (ELISA) is: IL-1 (0.5 ng/mL), IL-1 (3.5 ng/mL), IL-2 (0.3 ng/mL), IL-6 (35 ng/mL), TNF (0.2 ng/mL), TNF- (50 pg/mL), granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.4 ng/mL), OM (0.5 to 1 ng/mL) and IFN (150 pg/mL, corresponding to 3 to 4 U/mL of the recombinant IFN [Boehringer Mannheim,
Indianapolis, IN] used in these experiments). No bFGF is present in
the CM. RTCM were prepared by combining recombinant cytokines at the
concentrations described above. OM was purchased by R & D Systems
(Minneapolis, MN) or obtained by B.C. Nair (Advanced BioScience
Laboratories, Inc, Kensington, MD). All of the other cytokines were
purchased from Boheringer Mannheim.
Cell cultures.
HUVE cells (passage 5 to 10) were cultured as previously
described30-32 on gelatinized flasks in complete medium
composed of RPMI 1640, 15% fetal bovine serum (FBS), 45 µg/mL of
endothelial cell growth supplement (ECGS) (Collaborative Products,
Bedford, MA) and 30 µg/mL of heparin (Sigma), 1% nutridoma HU (100 × solution) (Boehringer Mannheim), 1% essential amino acids
(50 × solution) (GIBCO, Grand Island, NY), 1%
nonessential amino acids (100 × solution) (GIBCO), 1 mmol/L of
sodium pyruvate (GIBCO), 100 U/mL penicillin G-sodium, 100 mg/mL
streptomycin sulfate, 0.25 mg/mL amphotericin B (GIBCO).
Cytokine-treatment was performed by culturing HUVE cells for 5 to 6 days in the presence of TCM, RTCM, or IFN.
Animal experiments.
IFN-treated (102 U/mL), TCM-treated (1:4 dilution), or
untreated HUVE cells (3 × 106 cells in 200 µL of
media), were injected subcutaneously into the lower back (right side)
of Balb/c nu/nu athymic mice, in the presence or in the absence of Tat
(10 µg) as described previously.32 The negative control
(media in which the cells were resuspended) was injected into the left
side of the same mice, as previously described.31,32 Cells
or media were mixed with an equal volume (200 µL) of Matrigel
(Collaborative Biomedical Products) before inoculation.32
Mice were killed 6 days later and the sites of injection were evaluated
for the presence of macroscopic vascular lesions. Tissue samples were
taken from all inoculated sites and fixed in formalin for histologic
examination after hematoxylin and eosin (H & E) staining.
The histologic changes observed at the site of injection, blood vessel
formation, spindle cell proliferation, and edema were evaluated by
comparison with the negative controls and graded according to intensity
from 1 to 8 with the minimal alteration observed given a value of 1 (intensity value), as described previously.32
| |
RESULTS |
CD8+ T cells and monocytes-macrophages are the
predominant inflammatory cell types of KS and produce
IFN.
To analyze the type of infiltrating immune cells and the prevalent IC
production in KS, immunohistochemical analyses were performed on frozen
sections from both AIDS-KS and C-KS lesions and uninvolved tissues from
the same patients by using antibodies specific for CD4, CD8, CD14,
CD68, CD20, and HLA-DR and for the IC IL-1, TNF, and IFN.
A prevalent CD8+ T-cell infiltration and infiltration with
CD14+ and CD68+ monocytes-macrophages were
detected in all lesions examined and were more evident in early stage
lesions (Fig 1). A variable proportion of
CD4+ T cells was also found, whereas B cells
(CD20+) were few or absent in all lesions examined (data
not shown). This cell infiltration was associated with a detectable
expression of IL-1 and TNF (data not shown), as described
previously,60-62 but particularly with a high level of
expression of IFN (Fig 1). IFN was found expressed in 100%
(19/19) AIDS-KS and in 100% (3/3) C-KS lesions examined. Anti-IFN
antibodies stained mostly mononuclear cells, but also spindle-shaped
cells (Fig 1). In contrast, in uninvolved tissues, only some
mononuclear cells were stained (Fig 1). HLA-DR, which was evaluated to
estimate the cell activation and the biologic activity of IFN, was
expressed in all of the IFN+ KS lesions and tissues
tested, and, at a low level, in one uninvolved tissue in which IFN
was not detected. Positivity for HLA-DR was also strong in vessels and
endothelial cells of KS lesions.
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| Fig 1.
Expression of IFN, CD8, CD14, and CD68 in a
representative KS lesion (lower panels, original magnification × 400)
and uninvolved tissue (upper panels, original magnification × 1,000)
by immunohistochemistry (APAAP) as described in Materials and Methods.
Positivity for IFN (red stain) was mostly observed in mononuclear
cells, but also in spindle-shaped cells, as compared with uninvolved
tissues. A strong increase in CD8+ and
CD14+/CD68+ infiltrating cells, often with
a subendothelial localization, was also observed in KS lesions, whereas
these infiltrating cells are rare in uninvolved tissues. Similar
results were obtained in all KS lesions analyzed, but were prevalent in
early stage lesions.
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To identify the cell types producing IFN, double-staining
experiments were performed with anti-IFN and anti-CD8, -CD4, -CD14, -CD68, or anti-FVIII-RA antibodies. The results indicated that the
cells producing IFN (double positive cells) were mostly of the
CD8+ phenotype (Fig 2).
Spindle-shaped cells producing IFN had a CD14+ or
CD68+ phenotype, whereas endothelial cells
(FVIII-RA+) in vessels did not stain for IFN (Fig 2).
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| Fig 2.
Expression of IFN by CD8+,
CD14+, or CD68+ cells infiltrating KS
lesions. Examples of double-staining by immunohistochemistry (APAAP/PAP) of IFN and CD8, IFN, and CD14 or CD68, IFN, and FVIII-RA in a representative KS lesion. Similar results were obtained with other specimens. CD8+ cells (red stain) coexpressing
IFN (brown stain) had a mononuclear morphology (upper right panel),
whereas anti-CD14 or anti-CD68 antibodies (red stain), recognizing
monocytes-macrophages, costain IFN+ (brown stain)
spindle-shaped cells (lower left and right panels). In contrast,
anti-IFN antibodies (brown stain) do not stain
FVIII-RA+ vessels (red stain, upper right panel), but
IFN+ cells are often localized in the proximity of
vessels.
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IFN is the principal inducer of the KS spindle cell
phenotype.
Previous observations indicated that KS spindle cells represent a
heterogeneous population dominated by activated endothelial cells.4-7,63-68 IC and in particular IFN are known to
have profound effects on endothelial cells and to induce changes
generally described as activation,69-71 which are the same
phenotypic changes found in KS lesions. To investigate the role of IC
and of IFN in these changes, specific endothelial cell markers and
activation molecules were analyzed after culture of HUVE cells in the
presence of TCM that contain the same IC expressed in KS tissue. These
experiments were also performed with RTCM that was obtained by adding
together recombinant cytokines at the same concentration measured in
TCM with or without IFN, or in the presence of IFN alone
(103 U/mL) (Table 1).
Similar levels of CD34 and VE-cadherin were observed in HUVE cells
independently from the treatment. On the contrary, all cytokine
combinations (TCM, RTCM) and IFN alone downregulated FVIII-RA and
EN-4 expression (Table 1). This same pattern of marker expression,
including FVIII-RA downregulation, is found in KS cells both in vivo
and in vitro,55,68 and both IL-1 and IFN can
downregulate FVIII-RA expression.55,71,72 TCM and RTCM also
increased the expression of VCAM-1, ICAM-1, and ELAM-1 as found for KS
cells.55,67,68 IFN alone had a similar effect, although
less intense than in the presence of combined cytokines (Table 1). In
addition, IFN-treated cells expressed HLA-DR, another marker found
to be expressed in spindle cells and vessels of KS; in contrast, cells
exposed to TCM or RTCM stained negative due to the counteraction of
IL-1.73
Finally, as previously found with other cell types74,75
TCM-treated or IFN-treated HUVE cells acquired a typical spindle morphology indistinguishable from that of KS cells
(Fig 3). Thus, IFN can induce phenotypic
changes similar or identical to those found in spindle cells in vitro
and in most spindle cells of the lesions. However, this effect is
maximal in the presence of other IC that contribute to these changes
directly or by increasing IFN function.69,71
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| Fig 3.
IFN and TCM induce HUVE cells to acquire a spindle
morphology. Shown are HUVE cells (left panels, original magnification × 40; right panels, original magnification × 100) cultured under standard conditions (HUVE) or after 6 days of culture in the presence of TCM (TCM-HUVE) or 103 U/mL of IFN (IFN-HUVE).
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IFN induces endothelial cells to acquire angiogenic
properties and to induce KS-like lesions in nude mice.
Inoculation of cultured KS spindle cells in nude mice induces vascular
lesions of mouse cell origin closely resembling early KS.31,32,76 These KS-like lesions develop in response to
the cytokines produced by AIDS-KS spindle cells, such as bFGF, which mediates angiogenesis and spindle cell growth, and VEGF, which synergizes with bFGF in inducing angiogenesis and
edema30-32,50 (and F. Samaniego et al,
submitted). Angiogenic cytokine production, on the other
hand, is induced in vitro in KS cells or endothelial cells by TCM or
IC50,58,59 (and F. Samaniego et al,
submitted). To determine whether IFN alone could
induce normal endothelial cells to acquire the capability to promote
KS-like lesions, untreated, TCM-treated, or IFN-treated HUVE cells
were inoculated in nude mice (Fig 4 [see
page 959], Table 2). IFN-treated or
TCM-treated HUVE cells induced macroscopic vascular lesions in 41% and
59% of the inoculated mice, respectively. Histologic alterations
typical of KS such as angiogenesis, spindle cell growth, and edema were
present in 70% to 82% and 100% of the mice inoculated with
IFN-treated or TCM-treated cells, respectively. In contrast, no
lesions were induced by untreated HUVE cells (Fig 4A, Table 2). Tissue
samples from the sites inoculated with TCM-treated, IFN-treated
cells, or from untreated cells were then analyzed for bFGF expression
by immunohistochemistry (Fig 4B). No bFGF was detected in sites
inoculated with untreated HUVE cells, in contrast, high levels of bFGF
were found in sites inoculated with both TCM-treated or IFN-treated
HUVE cells. These results indicated that IFN induces normal
endothelial cells to acquire angiogenic, KS-promoting activity due to
induction of bFGF whose production is activated by IFN in cultured
endothelial cells.59 In addition, the presence of other IC
as in TCM increased the angiogenic effect of IFN consistent with in
vitro data of synergistic effects of combined IFN, IL-1, and TNF on
bFGF production.58,59 As both IFN and bFGF are expressed
in KS lesions (from all forms of KS), these data suggest that these
mechanisms are operative in vivo.
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| Fig 4.
IFN-treated or TCM-treated HUVE cells induce KS-like
lesions in nude mice. Lesion formation is associated with expression of
bFGF. (A) Shows examples of the histopathology (H & E staining, original magnification × 400) and (B) shows bFGF expression by immunohistochemistry in the same tissues from mice inoculated with
untreated HUVE cells (HUVE), TCM-treated HUVE cells (TCM-HUVE), or
IFN-treated HUVE cells (IFN-HUVE), respectively.
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Table 2.
IFN-Treated or TCM-Treated HUVE Cells Induce in Nude
Mice Vascular Lesions Closely Resembling KS That Are Increased by
the HIV-1 Tat Protein
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HIV-1 Tat protein increases the KS-like forming activity of
endothelial spindle cells induced by IFN or TCM.
Previous data indicated that the Tat protein of HIV-1 can increase the
frequency and aggressiveness of KS in HIV-1-infected individuals32 and may act as a progression factor. In fact, inoculation of mice with Tat alone has little or no effect. However, when Tat is injected in the presence of suboptimal amounts of bFGF,
synergistic angiogenic KS-promoting effects are observed and a higher
number of mice develop lesions as compared with injection of bFGF
alone.32 These are due to the enhancement by Tat of endothelial cell growth, migration, and invasion induced by bFGF and to
bFGF-induced expression of the integrins 51 and v3 that
function as the receptors for Tat.32,57 Thus, bFGF is required for the in vivo effect of Tat. Because TCM or IFN induce production of bFGF (Fig 4B) and expression of the same
integrins57 (and data not shown), this suggested that Tat
could exert its effect on KS lesion formation. To investigate this,
mice were inoculated with IFN-treated or TCM-treated cells in the
presence of Tat. As shown in Table 2, Tat increased the number of mice developing lesions from 41% to 60% with IFN-treated cells and from
59% to 100% with TCM-treated cells, respectively. In addition, Tat
enhanced each histologic alteration induced by treated cells (Table 2).
Thus, Tat can augment the angiogenic activity of TCM- or IFN-treated
endothelial cells and this results in enhancing effects on KS lesion
formation. This effect is maximal in the presence of other IC as shown
by the more potent effect of Tat on KS-like lesions induced by
TCM-treated cells. As Tat is relesased by HIV-1 infected
cells52,56,57,77 and is present in AIDS-KS lesions,32 these data support its role as a progression
factor for HIV-1-infected individuals and indicate that IFN alone
or, more efficiently, in combination with other IC renders the tissues responsive to the effect of Tat.
HHV-8 infection and expression of IFN and HLA-DR in
AIDS-KS and C-KS.
Herpesviruses are known to activate CD8 T cells and to induce
production of IFN.78-82 Thus, the presence
of HHV-8 in all forms of KS suggested that it may induce or contribute
to the local immune response and inflammatory cell infiltration that
leads to production of cytokines and in particular of IFN. To verify whether HHV-8 is detectable in the KS lesions and uninvolved tissues examined for IFN and whether it is the prevalent infectious agent as
compared with other herpesviruses, the same tissues were analyzed by
regular PCR and Southern blot or liquid hybridization for the presence
of HHV-8, EBV, HHV-6, HHV-7, and CMV. -Globin was used to confirm
that the DNA extracted from tissues was amplifiable. As shown in
Table 3, HHV-8 was detected in the majority
(86%) of both forms of KS analyzed (18/21). Specifically, HHV-8
sequences were amplified in 89% of AIDS-KS (16/18) and 67% (2/3) of
C-KS lesions examined. In addition, 40% (2/5) of the uninvolved
tissues examined were positive for HHV-8 specific amplification. When the PCR data were compared with the results of the IFN and HLA-DR staining, we observed that 100% of HHV-8+ KS lesions
examined expressed IFN (18/18) and HLA-DR (14/14), respectively. In
contrast, only 14% (3/21) and 12% (2/16) of the IFN+
and HLA-DR+ lesions, respectively, were negative for HHV-8
sequences.
View this table:
[in this window]
[in a new window]
|
Table 3.
Expression of IFN and HLA-DR in AIDS-KS, C-KS
Lesions, and Uninvolved Tissues and Correlation With the Presence
of HHV-8 and EBV
|
|
EBV was detected in 4/14 AIDS-KS (28%) and in 1/3 C-KS (33%) lesions
examined (Table 3). For AIDS-KS, all cases positive for EBV were also
positive for HHV-8 and expressed both IFN and HLA-DR. Surprisingly,
for C-KS, the case positive for EBV was consistently negative for HHV-8
by unnested PCR, but it was still positive for IFN or HLA-DR
expression. No other herpesviruses except for a small percentage of
HHV-6 (5%) and CMV (8%) were detected in the lesions examined and
they were associated with the presence of HHV-8 (data not shown).
Finally, IFN and HLA-DR were both found to be expressed in 2/2
(100%) HHV-8+ uninvolved tissues. In addition, IFN was
expressed in 2/3 (66%) and HLA-DR in 3/3 (100%) HHV-8-
uninvolved tissues, respectively. However, the levels of expression of
both markers and particularly of IFN were lower than in
HHV-8+ tissues (Table 3). Thus, IFN is highly expressed
by CD8+ and CD14+/CD68+ cells
infiltrating the lesions from both AIDS-KS and C-KS that contain HHV-8
and/or EBV specific sequences and these events are associated
with endothelial cell activation, as shown by HLA-DR staining of
spindle cells and vessels, which are also positive for other activation
markers such as ELAM-1, ICAM-1, and VCAM-1.68
| |
DISCUSSION |
The consistent presence of HHV-8 in tissues from patients with all
forms of KS8-12 and the high rate of infection in
individuals at risk of KS indicate that this virus plays an important
role in KS development.18,83-85 The specific role of HHV-8
in KS pathogenesis, however, has not yet been delineated. HHV-8
possesses genes encoding for potential transforming proteins, in
particular cyclin D, IL-8R, and bcl-2. Other viral genes encode for
proteins, like v-IL-6, that can act with paracrine mechanisms on
neighbor cells.21-23,86 These viral genes have been shown
to be functional and some display a transforming activity in vitro. In
addition, their homologs are present in herpesviruses with known or
suggested transforming activities, like EBV, herpesvirus Sahiri (HVS)
and CMV.87-89 These observations suggested that these viral
products may play a key role in the pathogenesis of KS. However, HHV-8
cyclin D, IL-8R, and IL-6 are expressed at very low levels or are
undetectable in KS tissues.21-23,26,28,33 In addition, it
is unclear whether these genes contribute to the transforming activity
of EBV and HVS whose transforming functions are encoded by other
genes.90-92 Furthermore, EBV-bcl-2 is expressed in cells
undergoing lytic infection after reactivation from
latency.93 Consistent with this, HHV-8 viral homologs are
induced at high levels in PEL cell lines after reactivation of lytic
infection by TPA.21,33 Because only a small percentage of
HHV-8-infected cells of monocytic-macrophagic origin undergo viral
lytic infection in KS tissues,33,42,45 the low levels of
expression of v-IL-8R, v-cyclin D, and v-IL-6 are consistent with
these functions being expressed in this small percentage of cells. In
contrast, the human IL-6 and bcl-2 are expressed at high levels in
KS.34,35 In addition, HHV-8 is absent in the only two KS
tumor cell lines obtained to date,36 and although
endothelial spindle cells present in KS lesions are latently infected
with HHV-8, they lose the virus on culture33,37-39,94-96
(and our unpublished data). Finally, HHV-8 does not seem to transform
cells in vitro.40
It appears therefore conceivable that HHV-8 may act in KS pathogenesis
also through indirect mechanisms, for example by activating the
expression of host molecules able to induce the KS spindle cell
phenotype and the cascade of events leading to KS lesion formation.
This is also in agreement with experimental and clinical data
indicating that, at least in early stage, KS is not a true cancer, but
an hyperplastic angiogenic proliferation that may regress.47-49 These considerations prompted us to identify
host factors triggering KS formation and to investigate their
correlation with HHV-8 infection.
Our results show that IFN may play a pivotal role in KS development.
IFN is strongly expressed in both AIDS-KS and C-KS lesions and in
HHV-8+ uninvolved tissues from the same patients. IFN
expression is associated with endothelial cell activation, as indicated
by the expression of HLA-DR and adhesion molecules in vessels and
spindle cells of the lesions. Although it is mostly produced by
infiltrating CD8+ T cells, IFN is also expressed by
spindle cells of macrophage origin with a subendothelial localization,
in agreement with previous studies with macrophages.97-98
Data from the report by Sirianni et al99
further support these findings by showing that a prevalent CD8+ T-cell infiltration is present in both AIDS-KS and
C-KS lesions, and that PBMC, tumor infiltrating lymphocytes, and
spindle cells of macrophage origin cultured from KS lesions produce
prevalently IFN.
IFN induces the formation of spindle cells with angiogenic activity.
Specifically, IFN promotes phenotypical and functional changes and
activities in endothelial cells closely resembling KS spindle cells
including the angiogenic activity and the angiogenic synergy with Tat.
In fact, IFN alone is sufficient to induce a modulation of marker
expression that is similar or identical to the pattern of markers
expressed by KS spindle cells and it is accompanied by the acquisition
of the typical spindle morphology. In addition, when normal endothelial
cells are treated with TCM or IFN alone, they acquire the capability
of inducing KS-like lesions and histologic alterations of mouse cell
origin, which are indistinguishable from those induced by KS cells. As
for KS cells, this is associated with the upregulation of bFGF
production in the inoculated mice, as shown in vitro58,59
and it is consistent with the presence of high levels of expression of
bFGF in all forms of KS.32 Finally, these effects are
increased synergistically by Tat demonstrating its role as a
progression factor in AIDS-KS, in fact, bFGF and Tat are both present
in AIDS-KS lesions and Tat increases the KS-forming activity of
bFGF.32 Further, Tat can amplify HHV-8 viral
load100 and can activate a further increase of IC (reviewed
in Chang et al101). All of the effects of IFN are
potentiated by the presence of additional IC that increase IFN
function or synergize with IFN. For example, IL-1 and TNF synergize
with IFN in activating bFGF expression and release.58,59 Similar enhancing effects are observed for adhesion molecule expression and spindle morphology.69-72,74,75 Thus, although IFN
alone is sufficient, other IC present in KS, such as IL-1 and TNF, cooperate with IFN to induce the histological and phenotypical features of the lesion.
IFN and HLA-DR expression correlate with the presence of HHV-8 in
involved or uninvolved tissues. Data from the accompanying paper by
Sirianni et al99 show that the infiltration of
CD8+ T cells and the presence of macrophages producing
IFN is associated with that of HHV-8 in PBMC, KS tissues, and
macrophagic spindle cells cultured from KS lesions of the same
patients. The blood of these patients contains spindle-like macrophagic
cells that are infected by HHV-8.43,44 This is consistent
with recent data indicating HHV-8 lytic infection in mononuclear cells
infiltrating KS lesions.42,45 These data therefore suggest
that an immune response to HHV-8-infected cells present in tissues
triggers or amplifies KS development through induction of IFN. It is
remarkable that one early C-KS lesion expressing both IFN and HLA-DR
was negative for HHV-8 (or contained viral DNA in such a low amount to
prevent its detection by unnested PCR), but it was infected by EBV. In
fact, EBV, as well as other herpesviruses, are known to activate
CD8+ T cells and to induce IFN
production.78-82 Indeed, an oligoclonal expansion of CD8
T+ cells has been described following EBV infection in
patients with HIV and in macaques infected with the simian
immunodeficiency virus.82,102,103 Although IFN and
HLA-DR expression are increased in HHV-8+ versus
HHV-8- tissues, a low production of IFN is also found in
HHV-8- uninvolved tissues from KS patients, suggesting that IFN expression may precede a detectable HHV-8 infection. As IFN has also been shown to act as a major mediator in recruiting cells into
the skin,104 this may represent a process to increase the tissue localization of HHV-8-infected cells, and it may explain why
IFN detection can precede HHV-8 detection. This would be in
agreement with recent evidence that HHV-8 prevalence and viral load can
increase with lesion progression.37,105
In conclusion, although other IC may cooperate in the pathogenesis of
KS, IFN seems to play a major role in KS development and this may be
in response to HHV-8 infection. In support of this concept are studies
that have shown that unstimulated106 or
activated107 purified blood mononuclear cell cultures from HIV-1-infected homosexual men with documented early phase infection produce more IFN than the seronegative controls. Furthermore, CD8
activation, generally accompanied by IFN production, is higher in
HIV-1 seronegative homosexual men than in healthy donors, as documented
by the increased serum levels of CD8 and soluble ICAM in these
individuals.108,109 These patients are also infected by
HHV-8 and are at high risk of KS development. Finally, the administration of IFN to KS patients has resulted in disease progression.110,111 Although it remains to be determined
whether HHV-8 itself can induce a CD8+ T-cell activation
and consequent IFN production, this may represent a pathway by which
this virus can trigger or amplify the development of KS.
| |
FOOTNOTES |
Submitted May 20, 1997;
accepted September 26, 1997.
Supported in part by a grant from Associazione Italiana Ricerca sul
Cancro (AIRC; Milan) and from the IX AIDS Project from the Ministry of
Health, Rome, Italy. V.F. was partially supported by Associazione
Nazionale per la Lotta contro l'AIDS, Ministry of Health in Rome,
Italy.
Address reprint requests to Barbara Ensoli, MD, PhD, Laboratory of
Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
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.
| |
ACKNOWLEDGMENT |
We thank E. Dejana (Istituto di Ricerche Farmacologiche "Mario
Negri," Milano, Italy) for the anti-VE-cadherin MoAbs; B.C. Nair
(Advanced BioScience Laboratories, Inc, Kensington, MD) for OM; P. Secchiero (Institute of Human Virology, Baltimore, MD) for the HHV-6
and HHV-7 PCR primers; V. Kao (Laboratory of Tumor Cell Biology
[LTCB], NCI) for technical help; G. Barillari (Department of General
Pathology, II University of Rome), P. Verani (Laboratory of Virology,
Istituto Superiore di Sanità, Rome) for helpful discussions, and
Angela Lippa for editorial assistance.
| |
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G. Barillari and B. Ensoli
Angiogenic Effects of Extracellular Human Immunodeficiency Virus Type 1 Tat Protein and Its Role in the Pathogenesis of AIDS-Associated Kaposi's Sarcoma
Clin. Microbiol. Rev.,
April 1, 2002;
15(2):
310 - 326.
[Abstract]
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P. Cassoni, A. Sapino, S. Deaglio, B. Bussolati, M. Volante, L. Munaron, A. Albini, A. Torrisi, and G. Bussolati
Oxytocin Is a Growth Factor for Kaposi's Sarcoma Cells: Evidence of Endocrine-Immunological Cross-Talk
Cancer Res.,
April 1, 2002;
62(8):
2406 - 2413.
[Abstract]
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M. Crowther, N. J. Brown, E. T. Bishop, and C. E. Lewis
Microenvironmental influence on macrophage regulation of angiogenesis in wounds and malignant tumors
J. Leukoc. Biol.,
October 1, 2001;
70(4):
478 - 490.
[Abstract]
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E. Toschi, G. Barillari, C. Sgadari, I. Bacigalupo, A. Cereseto, D. Carlei, C. Palladino, C. Zietz, P. Leone, M. Sturzl, et al.
Activation of Matrix-Metalloproteinase-2 and Membrane-Type-1-Matrix-Metalloproteinase in Endothelial Cells and Induction of Vascular Permeability In Vivo by Human Immunodeficiency Virus-1 Tat Protein and Basic Fibroblast Growth Factor
Mol. Biol. Cell,
October 1, 2001;
12(10):
2934 - 2946.
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S. Pati, M. Cavrois, H.-G. Guo, J. S. Foulke Jr., J. Kim, R. A. Feldman, and M. Reitz
Activation of NF-{kappa}B by the Human Herpesvirus 8 Chemokine Receptor ORF74: Evidence for a Paracrine Model of Kaposi's Sarcoma Pathogenesis
J. Virol.,
September 15, 2001;
75(18):
8660 - 8673.
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P. Rimessi, A. Bonaccorsi, M. Sturzl, M. Fabris, E. Brocca-Cofano, A. Caputo, G. Melucci-Vigo, M. Falchi, A. Cafaro, E. Cassai, et al.
Transcription Pattern of Human Herpesvirus 8 Open Reading Frame K3 in Primary Effusion Lymphoma and Kaposi's Sarcoma
J. Virol.,
August 1, 2001;
75(15):
7161 - 7174.
[Abstract]
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C. Sgadari, E. Toschi, C. Palladino, G. Barillari, D. Carlei, A. Cereseto, C. Ciccolella, R. Yarchoan, P. Monini, M. Sturzl, et al.
Mechanism of Paclitaxel Activity in Kaposi's Sarcoma
J. Immunol.,
July 1, 2000;
165(1):
509 - 517.
[Abstract]
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D. M. Aboulafia
The Epidemiologic, Pathologic, and Clinical Features of AIDS-Associated Pulmonary Kaposi’s Sarcoma
Chest,
April 1, 2000;
117(4):
1128 - 1145.
[Abstract]
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M. Sturzl, C. Hohenadl, C. Zietz, E. Castanos-Velez, A. Wunderlich, G. Ascherl, P. Biberfeld, P. Monini, P. J. Browning, and B. Ensoli
Expression of K13/v-FLIP Gene of Human Herpesvirus 8 and Apoptosis in Kaposi's Sarcoma Spindle Cells
J Natl Cancer Inst,
October 20, 1999;
91(20):
1725 - 1733.
[Abstract]
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M. S. Reitz Jr., L. S. Nerurkar, and R. C. Gallo
Perspective on Kaposi's Sarcoma: Facts, Concepts, and Conjectures
J Natl Cancer Inst,
September 1, 1999;
91(17):
1453 - 1458.
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G. Barillari, C. Sgadari, C. Palladino, R. Gendelman, A. Caputo, C. B. Morris, B. C. Nair, P. Markham, A. Nel, M. Sturzl, et al.
Inflammatory Cytokines Synergize with the HIV-1 Tat Protein to Promote Angiogenesis and Kaposi's Sarcoma Via Induction of Basic Fibroblast Growth Factor and the {alpha}v{beta}3 Integrin
J. Immunol.,
August 15, 1999;
163(4):
1929 - 1935.
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G. Barillari, C. Sgadari, V. Fiorelli, F. Samaniego, S. Colombini, V. Manzari, A. Modesti, B. C. Nair, A. Cafaro, M. Sturzl, et al.
The Tat Protein of Human Immunodeficiency Virus Type-1 Promotes Vascular Cell Growth and Locomotion by Engaging the alpha 5beta 1 and alpha vbeta 3 Integrins and by Mobilizing Sequestered Basic Fibroblast Growth Factor
Blood,
July 15, 1999;
94(2):
663 - 672.
[Abstract]
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E. A. Mesri
Inflammatory Reactivation and Angiogenicity of Kaposi's Sarcoma-Associated Herpesvirus/HHV8: A Missing Link in the Pathogenesis of Acquired Immunodeficiency Syndrome-Associated Kaposi's Sarcoma
Blood,
June 15, 1999;
93(12):
4031 - 4033.
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P. Monini, S. Colombini, M. Sturzl, D. Goletti, A. Cafaro, C. Sgadari, S. Butto, M. Franco, P. Leone, S. Fais, et al.
Reactivation and Persistence of Human Herpesvirus-8 Infection in B Cells and Monocytes by Th-1 Cytokines Increased in Kaposi's Sarcoma
Blood,
June 15, 1999;
93(12):
4044 - 4058.
[Abstract]
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G. Ascherl, C. Hohenadl, O. Schatz, E. Shumay, J. Bogner, L. Eckhart, E. Tschachler, P. Monini, B. Ensoli, and M. Sturzl
Infection With Human Immunodeficiency Virus-1 Increases Expression of Vascular Endothelial Cell Growth Factor in T Cells: Implications for Acquired Immunodeficiency Syndrome-Associated Vasculopathy
Blood,
June 15, 1999;
93(12):
4232 - 4241.
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P. Monini, F. Carlini, M. Stürzl, P. Rimessi, F. Superti, M. Franco, G. Melucci-Vigo, A. Cafaro, D. Goletti, C. Sgadari, et al.
Alpha Interferon Inhibits Human Herpesvirus 8 (HHV-8) Reactivation in Primary Effusion Lymphoma Cells and Reduces HHV-8 Load in Cultured Peripheral Blood Mononuclear Cells
J. Virol.,
May 1, 1999;
73(5):
4029 - 4041.
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N. Dupin, C. Fisher, P. Kellam, S. Ariad, M. Tulliez, N. Franck, E. van Marck, D. Salmon, I. Gorin, J.-P. Escande, et al.
Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma
PNAS,
April 13, 1999;
96(8):
4546 - 4551.
[Abstract]
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V. Fiorelli, G. Barillari, E. Toschi, C. Sgadari, P. Monini, M. Sturzl, and B. Ensoli
IFN-{gamma} Induces Endothelial Cells to Proliferate and to Invade the Extracellular Matrix in Response to the HIV-1 Tat Protein: Implications for AIDS-Kaposi's Sarcoma Pathogenesis
J. Immunol.,
January 15, 1999;
162(2):
1165 - 1170.
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Abstract
Introduction
Abstract