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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1364-1371
Proliferation and Apoptosis-Related Gene Expression in Experimental
Acquired Immunodeficiency Syndrome-Related Simian Lymphoma
By
Esmeralda Castaños-Vélez,
Thomas Heiden,
Marianne Ekman,
Joseph Lawrence,
Gunnel Biberfeld, and
Peter Biberfeld
From the Immunopathology Laboratory, Karolinska Institute/Hospital,
Stockholm, Sweden; the Swedish Institute for Infectious Diseases
Control and Karolinska Institute, Stockholm, Sweden; and
the Department of Medical Radiobiology, Karolinska
Institute, Stockholm, Sweden.
 |
ABSTRACT |
Lymphomas in 10 cynomolgus monkeys infected with a simian
immunodeficiency virus (SIVsm) were studied with regard to
proliferative activity and apoptosis-related gene expression. All were
diffuse large-cell lymphomas, showed mono or oligoclonality and a 9/10 diploid cellular DNA content. Expression of a simian homologue to
Epstein-Barr virus (HVMF-1) was shown in nine cases. The lymphomas showed moderate to high proliferative activity by Ki67 immunostaining and DNA flow cytometry, and a low number of apoptotic cells detected by
TdT-mediated dUTP nick-end labeling (TUNEL).
Immunohistochemistry showed abundant tumor infiltrating
TIA-1+ cytotoxic lymphocytes (CTL) and macrophages.
Bcl-2, Mcl-1, and also Bax and Bak, but not p53 were demonstrable in
the tumor cells by immunostaining. Our findings suggest a causal
relationship between HVMF-1 infection and a low apoptotic index of the
lymphomas due to the expression of Bcl-2. The apparent inefficient
function of tumor-infiltrating CTL could be due to inactivation of CTL and/or resistance of the lymphoma cells to CTL effects. The
tumors showed immunoreactivity for CD18, CD29, and CD49d, but not for CD11a, mimicking the phenotype of human Epstein-Barr virus
(EBV)-related lymphomas. In summary, our observations indicate a high
similarity between this simian model of acquired immunodeficiency
syndrome (AIDS)-related lymphomas (ARL) and human ARL and other
immunosuppression-related lymphomas.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
EPSTEIN-BARR VIRUS (EBV)-ASSOCIATED
lymphomas occur relatively frequently in immunosuppressed patients
either after organ transplantation or in persons infected with human
immunodeficiency virus (HIV)-1. Asian cynomolgus monkeys (Macaca
fascicularis) infected with simian immunodeficiency virus from
sooty mangabeys (SIVsm) develop disease conditions analogous to human
acquired immunodeficiency syndrome (AIDS), including disseminated,
extranodal, high-grade malignant, non-Hodgkin's B-cell lymphoma, in
approximately 30% of the diseased animals.1 We have
previously shown that this experimental model of simian AIDS-related
lymphoma (sARL) is characterized by aggressive extranodal presentation,
including central nervous system, B-cell origin, monoclonal/oligoclonal immunoglobulin gene rearrangements, and association with a simian EBV
homologue (herpes virus Macaca fascicularis,
HVMF-1).2-5 A more-aggressive clinical course was noted in
the oligoclonal compared with monoclonal sARL.5
Here we present novel studies on 10 sARL with regard to ploidy,
proliferative activity, and apoptosis-related gene expression and
HVMF-1 status. Our findings indicate that the cells in most of these
sARL have a diploid cellular DNA content, are moderately to highly
proliferative and appear to be protected from apoptosis by intrinsic
cellular factors. Furthermore, a possible intratumoral dysfunction in
cell-mediated immunity was suggested from the absence of tumor cell
destruction in spite of an abundant infiltration of cytotoxic
lymphocytes (CTL).
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MATERIALS AND METHODS |
Animals and biopsies.
Ten cynomolgus monkeys that had developed lymphoma after inoculation
with cell-free SIVsm (SIV strain SMM-3 originally obtained from Drs P. Fultz and H. McClure, Yerkes, Primate Center Atlanta, Georgia), were
included in the study. In addition, 12 infected cynomolgus monkeys that
developed simian AIDS (sAIDS) but not lymphoma were included for
comparison. At autopsy, tissue biopsies were frozen in liquid nitrogen
or fixed in buffered 4% paraformaldehyde (PFA).
Monkey lymphoma cell line SL-C18.
A cell line, SL-C18, was established from one lymphoma (number 10, Table 2) after culture in RPMI supplemented
with 10% fetal calf serum (FCS), penicillin, and streptomycin. This
cell line did not contain or produce SIV when tested by polymerase
chain reaction (PCR) (data not shown). Immunophenotyping of the cells was performed by fluorescence-activated cell sorting (FACS) analysis and by immunohistochemistry on cytospin preparations as described previously6 and below for frozen sections.
Immunohistochemistry.
Before immunostaining PFA-fixed, paraffin-embedded tissue sections were
deparaffinized, rehydrated, and microwave heated for 5 minutes in
citrate buffer (pH 6.0), followed by quenching of endogenous peroxidase
activity by pretreatment with 0.3% hydrogen peroxide. The sections
were incubated with primary monoclonal antibody or antiserum overnight
at 4°C.
Immunostaining of frozen sections was performed as previously
described.6 Bound antibody on paraffin and frozen sections was detected with a biotinylated secondary antibody, horse antimouse (Vector Laboratories Burlingame, CA), or swine antirabbit (Dako AB,
Glostrup, Denmark), followed by avidin biotin-peroxidase complexes (ABC) and 3,3 diaminobenzidine (Sigma-Aldrich, MS, USA) as
chromogen. Incubation with phosphate-buffered saline (PBS) instead of
the primary antibody was used as negative control. Optimal performance of the respective antibodies was evaluated on sections of human hyperplastic tonsils and lymph nodes of SIV-infected monkeys. The panel
of primary antibodies used is described in
Table 1. The intensity of the staining was
scored subjectively from 1+ to 4+ corresponding (1+) to less than 20%
positive cells in the section, (2+) 20% to 50%, (3+) 50% to 75%,
and (4+) if more than 75% of the cells were stained.
In situ hybridization (ISH) for Epstein-Barr virus encoded RNAs
(EBER)-EBV.
EBV-EBER RNA was detected by ISH on standard paraffin sections using a
commercial kit (Dako, Glostrup, Denmark) as previously described.5
PCR for immunoglobulin heavy-chain (IgH) variable, diversity,
joining regions (VDJ) rearrangements.
DNA was prepared from 5 to 10 paraffin sections (5 µm/each) by
digestion for 3 to 5 hours with proteinase K (250 µg/mL), (Boehringer Mannheim, Mannheim, Germany), in 50 mmol/L Tris buffer pH 8.5, with 1 mmol/L EDTA and 0.5% Tween 20 followed by phenol-chloroform extraction
and precipitation with ethanol. The following primers were used that
amplified DNA sequences of the human complementary determining region 3 (CDR3) by a seminested PCR as previously described7:
FR3A: 5'CTG TCG ACA CGG CCG TGT
ATT ACT G3' LJH : 5'AAC TGC AGA GGA GAC GGT GAC
C3' VLJH: 5'GTG ACC AGG GT(AGCT) CCT TGG CCC
CAG3' In the first part of the seminested PCR, the reaction mixture contained: 66 µmol/L dNTPs, 10 pmol/L of each primer
(FR3A and LJH), 1 unit Taq polymerase and 0.1 µg DNA in PCR reaction
buffer containing 2.5 µmol/L Mg2+ (PE Applied Biosystems,
Foster City, CA). For the second part of the PCR, the same reaction
mixture was used with the primers FR3A and VLJH and the PCR product
obtained from the first run diluted 1:20. The reactions were performed
in a PTC200 thermocycler (MJ Research Inc, Watertown, MA). DNA was
initially denatured at 95°C for 2 minutes, followed by 20 cycles of
denaturation at 95°C for 10 seconds, annealing at 60°C for 30 seconds and elongation at 72°C for 30 seconds, with a final
extension step at 72°C for 5 minutes. For the second part of the
seminested PCR identical conditions were used. The amplified DNA was
electrophoresed in a 10% polyacrylamide gel, stained with SYBR-green
nucleic acid gel stain (Molecular Probes, Leiden, Holland) and
visualized by fluorescent excitation with ultraviolet (UV) light.
DNA flow cytometric analysis of cell nuclei.
A 90-µm thick paraffin section from each biopsy was processed
according to a previously described8 formalin-protease
enucleation technique to obtain suspensions of single-cell nuclei. An
adjacent 5 µm section stained with hematoxylin-eosin was examined for
histological control. DNA analysis was also performed on nuclei from
the monkey lymphoma cell line and from peripheral blood mononuclear
cell (PBMC) of a healthy cynomolgus monkey fixed and prepared as the biopsy material omitting the paraffin embedding. The suspended cell
nuclei were stained with diamidinophenylindole (DAPI) and analyzed in a
PASII flow cytometer (Partec, Münster, Germany) equipped with a
mercury-arc lamp. The fluorescence of DAPI was excited at 365 nm and
measured above 435 nm. At least 40,000 cell nuclei of each specimen
were evaluated per histogram. The Multicycle program (Phoenix Flow
Systems, San Diego, CA) was used for cell cycle calculation.
TdT-mediated dUTP nick-end labeling (TUNEL) assay for apoptosis.
TUNEL was performed on 4 µm thick paraffin sections and on
suspended-cell nuclei (see above) using an in situ cell death detection kit according to the manufacturer's instructions (Boehringer Mannheim, Mannheim, Germany).
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RESULTS |
Clinical Histological and In Situ Observations
Clinical findings on the studied SIV-infected monkeys with and without
sARL are summarized in Table 2. The 10 sARL were disseminated non-Hodgkin's lymphoma with nodal and extranodal involvement. According to the REAL classification, all the tumors corresponded histologically to diffuse large B-cell lymphomas (DLCL). The time between SIV infection and death of monkeys with sARL varied from 7 to
28.5 months (209 to 856 days). The mean percentage of CD4+
cells in peripheral blood on the day of death was 8.2% (range 26% to
1%) for the sARL animals and 9.9% (range 23% to 1%) for those
without lymphoma. No significant difference in the percentage of
CD4+ cells at autopsy was found between the sARL and the
control (sAIDS) group of 12 SIVsm-infected monkeys without lymphoma but
euthanized for other AIDS-related morbidity (P = .92).
Furthermore, the rate of decline of the percentage of CD4+
cells in the two groups was not significantly different (P = .5) (Table 2 and Fig 1).
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| Fig 1.
Changes in the level of blood CD4+ cells
(percentage) during SIV infection in (A) eight cynomolgus monkeys that
developed lymphoma and in (B) 12 monkeys that died of other
AIDS-related causes.
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In situ hybridization for EBER-EBV showed the presence of a simian EBER
homologue in most tumor cells in 9 of the 10 lymphomas. The
EBER lymphoma developed in a monkey that was
serologically negative for HVMF-1 (data not shown).
Ploidy and Proliferation Analysis
The results of DNA flow cytometric analysis of the 10 primary lymphomas
studied are summarized in Table 3, and
showed intermediate to high fractions of proliferative cells indicating
a variable moderate to high rate of proliferation (percentage of S + G2
phase cells, range: 8.45 to 37.2%), which correlated with the results of immunostaining with Ki67 (proliferation nuclear antigen)
(Fig 2). Nine of the tumors
and the cell line showed a diploid cellular DNA content. In one case
two discrete aneuploid tumor populations were found at the different
tumor localizations (mediastinum, kidney, endocardium). This tumor
showed a monoclonal VDJ rearrangement by seminested PCR, indicating
that the two aneuploid populations originated from the same clone.
Interestingly, this tumor was the only HVMF-1 case
as mentioned above.
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Table 3.
Ploidy, Proliferation and Apoptosis Analysis by Flow
Cytometry of sARL (1-10), a Cell Line (SL-C18), and Normal Tissues
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| Fig 2.
Immunostaining for proliferation antigen (Ki67)
in a sARL showing numerous reactive lymphoma cells (×500).
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Ig-Gene Rearrangements (Clonality) and Immunophenotyping
VDJ PCR analysis of nine primary lymphomas and the cell line (derived
from the lymphoma case number 10) showed monoclonal rearranged VDJ DNA
segments (size 80 to 120 bp) in seven of the primary tumors and in the
cell line. Two cases appeared as oligoclonal with more than one
discrete VDJ band of comparable intensity. The mono and oligoclonal
cases did otherwise not differ with regard to clinical, immunological,
and molecular features (Fig 3).
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| Fig 3.
Gel of VDJ-Ig-PCR amplimers of lymphoma tissues from
SIV-infected monkeys. Lanes 3 and 5 correspond to oligoclonally
rearranged lymphomas. Lanes 1, 2, 4, 6, 7, 8, and 9 show monoclonal
rearrangements as well as lane 10 that contains DNA from the
sARL-derived cell line SL-C18. Lanes 11 and 12 are DNA from tissue
controls. Lane 11 corresponds to a tumor-free lymph node from one of
the animals that developed lymphoma and lane 12 to a nonlymphoid tissue
(kidney) from the same animal. The variable intensity of the bands
displayed in this gel appears to be related to a variable amount of
nontumor cells in each lymphoma case.
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In all tumors at least 50% of the cells expressed strongly the
pan-B-cell markers CD20 and CD23. The cell line SL-C18 also expressed
these markers.
All lymphomas showed conspicuous, diffuse infiltrates of
CD3+ cells, which to a large extent expressed the antigen
TIA-1 of cytotoxic granules, observed as a cytoplasmic, granular
pattern often in contact with the cell membrane
(Fig 4).
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| Fig 4.
Immunostaining of a lymphoma showing in (A) abundant,
infiltrating CD3+ lymphocytes and in (B) cells expressing
the TIA-1 (cytotoxic-related) antigen in an adjacent section (×500).
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Eight of the 10 lymphomas were also markedly infiltrated by macrophages
(CD68+). In 1 lymphoma, SIV was clearly demonstrable by
immunostaining apparently mostly in infiltrating macrophages
(Fig 5). In contrast, tumor-free lymph
nodes from all lymphoma monkeys were found to react for SIVp27
predominantly within follicles/germinal centers.
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| Fig 5.
Immunostaining showing SIVgag p27 expression in a
multinucleated giant cell infiltrating a sARL (×500).
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Apoptosis-Related Gene Expression
Bcl-2 gene family (Table
4).
Bcl-2 was variably expressed in most of the tumor cells in 9 of 10 lymphomas (Fig 6). The
Bcl-2 lymphoma was the only one displaying strong
reactivity for Mcl-1 in most tumor cells. Bax and Bak proteins were
variably expressed in all lymphomas, both in tumor and nontumor cells.
p53 and Waf-1.
Similar immunostaining patterns were found for p53 and Waf-1 in all
lymphomas. The few (approximately 1 per 1000) reactive cells apparently
corresponded to infiltrating, nontumor lymphocytes.
Adhesion Molecules
 1 integrins.
The 1 common subunit (CD29) was strongly expressed in tumor and
nontumor cells of six cases examined by immunostaining of frozen
sections as well as on the cells from the cell line. The  4 integrin
subunit (CD49d) was also expressed with a distribution pattern similar
to that of CD29, whereas the 5 integrin subunit (CD49e) was in
comparison weakly expressed both in tumor and nontumor cells.
VCAM-1 (CD106), a ligand of 41, was expressed in some of the
tumor cells with variable intensity, but not demonstrable on endothelial cells in tumor and nontumor areas.
2 integrins and their ligands.
In six cases available for immunostaining and in the cell line SL-C18,
both tumor and nontumor cells showed reactivity for the 2 integrin
subunit (CD18), whereas the L (CD11a), M (CD11b), and X
(CD11c) were not demonstrable on the tumor cells. In five out of six
cases the tumor cells showed weak immunostaining for ICAM-1 (CD54),
whereas ICAM-2 (CD102) and ICAM-3 (CD50) were negative. CD102 was
strongly expressed on endothelial cells and macrophages.
The Fas antigen CD95 was apparently expressed in some of the
infiltrating lymphocytes, but not by the tumor cells of any lymphoma.
Apoptosis
In paraffin sections of all lymphomas, apoptotic cells, often in small
clusters, were observed by the TUNEL assay. These cells usually had
morphological changes consistent with late stages of apoptosis
(apoptotic bodies) and were often observed within macrophages
(Fig 7). Cells in early stages of apoptosis
appeared morphologically usually to correspond to lymphoma cells. The
percentage of TUNEL+ cell nuclei, evaluated by flow
cytometry, varied between 1.25% and 24.2% (Table 3). The highest
value was observed in the HVMF-1 and Bcl-2 lymphoma.
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| Fig 7.
Apoptotic cells shown by the TUNEL assay in a sARL. Note
some apoptotic bodies phagocyted by macrophages (×500).
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A statistically significant correlation between the percentage of
apoptotic cells in the lymphoma tissues and the survival time (DPI) of
the monkey after SIV infection was found in 9 of the 10 cases
(P < .01) (Table 3). The last lymphoma (case number 10 in
Tables 2 and 3) was not included in this evaluation because it
developed in a SIV-infected monkey previously vaccinated with a
chimeric SIV that expresses HIV-1-type envelope (SHIV).
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DISCUSSION |
Our observations clearly indicate that the studied sARL-like human ARL
in general have clinical, virological, immunological, and cell
biological features of high-grade lymphoma. Interestingly, the
tumorigenicity of the sARL is apparently more related to their low
endogenous and host-induced apoptotic rate than to their moderate proliferative activity. The low apoptotic index of these lymphomas appears to be related to a high expression of Bcl-2, suggesting that
the proapoptotic factors Bax and Bak, also shown to be expressed, are
probably functionally inactivated by heterodimerization.9 The observed Bcl-2 overexpression is of particular interest because it
may interfere with the translocation of p53 from the cytosol to the
nucleus,9 and could thereby play a role in the inactivation of the wild-type p53, contributing to the protection of the tumor cells
from programmed cell death. However, other antiapoptotic effects of
Bcl-2 could also be considered. The overexpression of Bcl-2 in the sARL
may be related to the presence in the lymphoma cells of the previously
described simian homologue to EBV HVMF-1. This was clearly indicated by
the presence of EBER and of the HVMF-1 homologues to EBNA 1 and 2 (EBV
nuclear antigens) in the sARL cells.10 Thus, EBNA-2 of
human EBV can induce the expression of LMP-1, which may upregulate
Bcl-2 expression.11 It appears thus significant that the
only lymphoma case negative for the expression of Bcl-2 did not carry
HVMF-1 and developed in a monkey serologically negative for HVMF-1 both
before SIV infection and at autopsy. These findings suggest that as
with EBV, HVMF-1 EBNA2-like molecules may upregulate Bcl-2.
Some studies have shown that Bcl-2 is more often expressed in non-ARL
(69%) compared with ARL (36%), and that demonstration of LMP-1 in ARL
correlates with high levels of Bcl-2 expression.12 Furthermore, it appears that Bcl-2 expression correlates with a lower
proliferative activity in non-AIDS high-grade human non-Hodgkin's lymphomas.13 This is corroborated by our findings of a
correlation between Bcl-2 expression and a moderate proliferative
activity (S+G2 phase) in 9 of 10 tumors studied, in agreement with the concept that Bcl-2 can interfere with the cycling of
cells.9 Although the prognostic significance of Bcl-2
expression in human DLCL is controversial, some studies indicate that
Bcl-2 expression is a strong predictor of poor clinical outcome in
human DLCL.14 Correspondingly, the only lymphoma in our
study that did not express demonstrable Bcl-2 had a high apoptotic
index and a clinically less-aggressive behavior despite a high
proliferative rate (33.6% S+G2) and aneuploidy, (case 9 in Tables 2
and 3). Spontaneous simian non-AIDS-related lymphomas have not
occurred in our primate center and thus were not available for comparison.
There was a statistically significant (P < .01) correlation
between the percentage of apoptotic cells in the sARL, and the induction time (clinical presentation) postinfection of the lymphomas. Although most animals with sARL were euthanized within 2 to 3 weeks
after tumor presentation, all lymphomas were in stage IV and showed
pathological features of high-grade lymphomas (DCLC) corresponding to a
clinical end stage. In this statistical analysis we excluded the case
number 10 (Tables 2 and 3) that had been vaccinated with a chimeric
SIV/HIV (SHIV-4)15 before infection with SIVsm.
CTL can be specifically identified with a monoclonal antibody (TIA-1)
reacting with the membrane of the cytotoxic granules.16 Thus, studies have shown an increased number of TIA-1+ CTL
in lymph nodes of HIV-infected patients possibly related to increased
CTL activity in these patients.17 Interestingly, our
findings of a marked infiltration of CD3 and TIA-1+ cells
in the absence of adjacent apoptosis or necrosis, may indicate a
functional impairment of CTL responses in these tumors and/or reflect effects of soluble tumor-derived factors. Accordingly, as
previously shown,18 cells expressing EBNA-1 and very likely also the homologue in HVMF-1, may escape from cytotoxic T-lymphocyte surveillance. The Gly-Ala repeats present in EBNA-1 protein generate an
inhibitory signal that interferes with antigen processing and major
histocompatibility complex class I-restricted
presentation.18 It is therefore likely that EBNA-1 of
HVMF-1 has a corresponding effect in sARL, reflected in decreased CTL
efficiency and tumor progression. However, the specificity and
functional capacity of the lymphoma infiltrating CTL has not yet been
directly characterized. In addition, it has been shown that CTL
activity can also be modulated by various cytokines derived from
malignant and EBV-transformed B-lymphocytes.19
The possibility of Fas-FasL-mediated antitumor effects does not appear
likely from the apparent lack or low expression of CD95 in the B and T
lymphocytes of these lymphomas.
The expression of the CD95 ligand, CD40 and CD152 (CD40 ligand) and CD8
was not possible to assay because no suitable cross-reacting antibodies
for paraffin-embedded tissues are available.
In this study, we also confirm and extend our previous results on the
expression of adhesion molecules by the sARL.10 The strong
reactivity for 1 (CD29) and 4 (CD49d), but not for L (CD11a),
M (CD11b), and x (CD11c) integrin subunits reflects a phenotype
intermediate between that of Burkitt's lymphoma cells and other
EBV-related non-Hodgkin's lymphomas.20
At present we have found only one sARL case not associated with HVMF-1.
The species association of this herpesvirus was confirmed by
preliminary serological studies, showing the presence of anti-HVMF-1 antibodies in 30 out of 31 monkeys with lymphoma and in 28 of 31 cynomolgus monkeys without lymphoma (data not shown), suggesting a high
frequency of infection in wild cynomolgus monkeys with this simian EBV
homologue like EBV in humans. In human ARL, association with EBV was
shown in 30% to 50% of the cases,21 compared with 96% of
sARL association with HVMF-1. This may indicate a higher B-cell-transforming activity of HVMF-1 compared with human EBV. The
latent membrane protein 1 (LMP-1) is related to the oncogenic potential
of EBV.22 We have at present, not been able to show any
cross-reacting analog to LMP-1 in HVMF-1.10 However, HVMF-1 can immortalize monkey but not human cells to grow in vitro as lymphoblastoid cell lines (unpublished data), suggesting the effect of
a functional analog to LMP-1 in HVMF-1. Further studies on the
sequencing and characterization of this monkey herpes virus are
necessary to elucidate this question.
Molecular studies have described clonal integration of HIV in
tumor-associated macrophages in a variety of HIV-related neoplastic processes.23 Furthermore, the presence of SIV in tumor
cells of oligoclonal B-cell and in a T-cell sARL was recently also
reported.24 These findings suggest the possibility that SIV
may be directly involved in the process of B or T lymphomagenesis in
sAIDS. However, a transforming, oncogenic potential of SIV alone has
never been shown. By immunohistochemistry, we were able to show SIVgag
p27 only occasionally in the tumor-infiltrating macrophages, but never associated with lymphoma cells (Fig 5). Furthermore, we have tested several cell lines derived from different sARL by PCR for the presence
of SIV with negative results. In summary, it appears from our
observations that HVMF-1 is playing a central oncogenic role in the
pathogenesis of most sARL. Nevertheless, one of the sARL in this study
was negative for HVMF-1 indicating that also other tumorigenic factors,
possibly other viruses, could be involved in the development of some of
these lymphomas.
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ACKNOWLEDGMENT |
The skillful technical assistance of Reinhold Bentin is gratefully
acknowledged. Monkeys no. 2, 4, and 8 were kindly supplied by Disa
Böttiger and Bo Öberg, Karolinska Institute, Stockholm, Sweden, at the time of lymphoma diagnosis.
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FOOTNOTES |
Submitted March 31, 1998; accepted October 12, 1998.
Supported by the Swedish Cancer Society, the Swedish Medical Research
Council, and the Karolinska Institute.
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 Peter Biberfeld, Immunopathology
Laboratory, Karolinska Institute/Hospital, CCK, R8, plan 03, S-171 76, Stockholm, Sweden; e-mail: E.C-Velez{at}onkpat.ki.se.
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Abstract
Introduction