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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3159-3163
CONTROVERSIES IN HEMATOLOGY
Kaposi's Sarcoma-Associated Herpesvirus and Multiple Myeloma:
Lack of Criteria for Causality
By
Karin Tarte,
Yuan Chang, and
Bernard Klein
From INSERM U475, Montpellier, France; the Department of Pathology,
College of Physicians and Surgeons, Columbia University, New York, NY;
and the Unite de Therapie Cellulaire, CHU Montpellier, Hopital Saint
Eloi, Montpellier, France.
 |
INTRODUCTION |
RETTIG ET AL1 RECENTLY reported the
detection of Kaposi's sarcoma-associated herpesvirus (KSHV) DNA as
well as KSHV viral interleukin-6 (vIL-6) transcripts in cultured bone
marrow (BM) stromal dendritic cells (DC) of patients with multiple
myeloma (MM). In a follow-up study, this same group used KSHV ORF72
(v-CYC) in situ hybridization and KS330233 polymerase chain
reaction (PCR) to detect the virus in fresh BM biopsies of MM
patients.2 Given the general consensus that IL-6, mainly
produced by BM stromal cells, is a major growth factor for malignant
plasma cells in the active stage of the MM3 and because the
viral homolog of IL-6 is able to substain survival and proliferation of
myeloma cells,4 these data provided a plausible and
convenient model for MM pathogenesis. The putative role of KSHV in the
emergence of MM was also emphasized by the detection of KSHV DNA in
cultured stromal DC of 2 of 8 patients with monoclonal gammopathy of
undetermined significance (MGUS), a finding that could be used to
explain transformation to MM in 25% of MGUS.1 Berenson's
group also reported detection of KSHV DNA in peripheral blood
DC5 and in apheresis cells from patients treated with
cyclophosphamide and growth factors for hematopoietic precursor
mobilization.6 Furthermore, Berenson's group has claimed
that KSHV not only is involved in the pathogenesis of MM, but also is
involved in another late B-cell disorder, Waldenstrom macroglobulinemia.7
The determination of whether an infectious agent is causally related to
a disease was first formally codified by Robert Koch in the famed
Koch's postulates. These criteria served early microbiologists well.
However, in the present era, when newly discovered pathogens are not
easily cultivated and the detection of agents may depend on exquisitely
sensitive molecular techniques, scientists have looked to other
guidelines. A.B. Hill's epidemiologic criteria for causation, now
widely used to distinguish a causal from a noncausal association, is
one such set of guidelines.8 According to Hill's criteria,
evidence for causality depends on (1) strength of association, (2)
specificity, (3) temporality, (4) consistency/reproducibility, (5)
biologic gradient, (6) biologic plausibility, and (7) experimental evidence. Clearly, all of these criteria cannot be fulfilled for every
proposed disease association; however, they can provide a systematic
approach in examining this issue. In a little over 1 year since the
initial report of Rettig et al1 that hypothesized that KSHV
causes MM through infection of BM DC and elaboration of vIL-6 paracrine
effects, various laboratories have conducted investigations
predominently dealing with the establishment of strength of association
and consistency/reproducibility. The majority of the studies that have
accumulated fail to confirm this attractive hypothesis. Because KSHV
has been controversially involved in several diseases,9 we
will summarize the published data in an attempt to clarify the
association between KSHV and MM.
| |
KSHV AND BM STROMAL CELL CULTURES |
In their first report, Rettig et al1 described that stromal
cell cultures of MM patients contained KSHV ORF26 DNA by using unnested
PCR to amplify a 233-bp product (KS330233) and expressed vIL-6 by using reverse transcription-PCR (RT-PCR) for ORF
K2. This suggested that at least two noncontiguous KSHV ORFs were present in BM stromal cell cultures of patients with MM. In a subsequent report, the same group detected and sequenced KSHV ORF65 and
ORF72 in MM samples. In addition to detecting KSHV DNA by PCR, in situ
hybridization of KSHV ORF26 resulted in positive cytoplasmic
localization in a majority (nearly 100%) of stromal cultured
cells.1 This high rate of positivity of a lytic phase gene
in the cytoplasm is incompatible with sustainable maintenance of these
stromal cell cultures, because viral lytic program equates with
imminent host cell lysis. Aside from virologic considerations, the
presence of at least one copy of KSHV in each of the cultured stromal
cells would allow for Southern detection of viral DNA, such as can be
seen in KS lesions. To date, no evidence of positivity has been
produced by Southern analysis.
Four independent studies have failed to confirm the high rate of
infection reported initially. In three studies, KSHV DNA was detected
in only 1 of a total of 34 stromal cell cultures.10-12 The
single positive case was only positive using unnested
KS330233 PCR, which allows detection of approximately 10 KSHV genome copies per 0.2 µg of DNA,13 but was negative
by PCR using primers amplifying other ORFs and on immunostaining for
vIL-6. In the fourth study, Tisdale et al14 obtained BM
stromal cells from 25 normal subjects and 30 MM patients and assayed
them for KSHV infection. BM stromal cells were obtained using various
culture conditions.14 In a nested PCR assay determined to
detect approximately 3 KSHV genome copies per 200,000 cells, 60% of MM
samples were positive for KSHV ORF26 DNA (KS330). However, the same
sequence was also detected in 44% of samples from normal human
controls and in 85% of samples from rhesus macaques. Only 2 of 15 MM
and 2 of 21 control samples gave a reproducible weak signal in repeat
experiments. Nested PCR is exquisitely sensitive but also prone to
contamination, and these results suggest that, if the detection of
KS330 was not a false-positive, the target abundance was at the limit
of PCR detection. Furthermore, despite similar nested PCR
sensitivities, Tisdale et al14 failed to amplify two other
KSHV ORF sequences (ORF75 and ORF72). To explain these results, Tisdale
et al14 suggest the presence of another herpesvirus that
shares the KS330 sequence with KSHV and that is found in very low
levels in healthy donors' and MM patients' BM stromal cells. Finally,
an argument that detection of KSHV depends on culture conditions is not
supported by the preceeding reports, because the percentage of
KSHV-positive samples was not higher when stromal cells were cultured
according to Rettig's protocol. Taken together, these data from four
independent studies do not confirm a majority of cultured stromal
dendritic cells from MM patients to be infected with KSHV and neither
can at least two KSHV ORFs be reproducibly detected.
| |
KSHV AND FRESH BM SAMPLES |
In seven studies, including the initial work of Rettig et al, KSHV DNA
was undetectable in fresh BM aspirates (1 positive sample of
133) by unnested PCR.1,10-12,15-17 The only
patient positive for KSHV by PCR in these studies was also seropositive
for the virus.17 In response, Berenson has suggested that
heparin, which was used to harvest BM, could inhibit Taq polymerase and
must be removed by heparinase to allow KSHV sequence amplification. However, Perna et al12 performed their PCR on 22 DNA
samples extracted from EDTA-treated BM aspirates, and two recent
studies have clearly demonstrated the absence of a KSHV PCR inhibitor in negative BM samples.18,24 Thus, no study has reported
the presence of KSHV DNA in BM aspirates from MM patients, despite the
use of very sensitive PCR assays.
To explain these negative results, it has been further suggested that
the KSHV-infected cells adhere to bone and cannot be harvested by
aspiration. In agreement with this explanation, Said et al2
showed by ORF72 in situ hybridization that 2% to 10% of cells in BM
biopsies were infected with KSHV in 17 of 20 MM patients. By using
either Southern blotting of unnested PCR amplification products or
nested PCR, two studies failed to amplify the KS330 sequence (ORF26) in
BM biopsies from MM patients (1 positive sample of
18).11,19 In two other studies, ORF26 amplification could be detected in a majority of patients (23/30); however, detection required either two rounds of amplification (2 × 30
cycles)20 or 45 cycles of PCR.21 Because the
sensitivity of the PCR was not assessed and amplification of other ORFs
was not verified in these reports, it is not possible to draw a
definitive conclusion concerning KSHV infection in these cells.
Nevertheless, no report has confirmed that a high percentage of cells
(2% to 10% according to Said et al2) are infected with
KSHV in BM biopsies of MM patients.
The lack of KSHV detection in patients with MM could be due to strong
humoral and cell-mediated immune control of this infection. Such an
immune control is well-documented in acquired immunodeficiency syndrome
(AIDS)-related and posttransplant KS patients.22,23 The
lack of serological prevalence in MM does not support a strong humoral
response (see below). Furthermore, the lack of KSHV DNA detection in MM
patients with severe T-cell deficiency does not support a strong
T-cell-mediated control. Indeed, we studied 10 patients treated with
double high-dose chemotherapy associated with autologous
transplantation of purified CD34+ cells.24
These patients had less than 200 CD4+/µL for up to 1 year
in association with biological and clinical reactivation of herpesvirus
infections (2 varicella, 1 herpes simplex, 1 herpes zoster, and 6 patients with antigen positivity for cytomegalovirus). However, despite
the use of a sensitive PCR (detection of <5 KSHV genome copies in
150,000 cells) and the lack of KSHV PCR inhibitors, KSHV DNA could not
be detected in any of the 30 BM aspirates collected 90, 180, and 360 days after the second autograft. Berenson reported that KSHV was
present in BM biopsies from untreated patients and from patients in
relapse but not in BM biopsies from patients in remission.2
However, the lack of KSHV detection in these patients with T-cell
immunodeficiency could not be explained by an induction of complete
remission, because 4 of the 10 patients relapsed during the first year
after treatment.24
| |
EPIDEMIOLOGICAL AND SEROLOGICAL STUDIES ARGUE AGAINST AN ASSOCIATION
BETWEEN KSHV AND MM |
KSHV and non-AIDS KS are found at a higher incidence in
Italy,25 but this is not the case for MM.26
Recently, a comparison of the incidence rates of KS and MM in different
populations worldwide, including the United States, indicates that they
do not correlate.27 Immunofluorescence and immunoblot
seroassays allow the detection of antibodies against KSHV in 80% to
90% of KS patients at an early stage of infection.25,28-30
Among the 15 serological studies published to date, only one reported
an increased seroprevalence for KSHV in MM patients (81%) in
association with low antibody titers.31 In this study,
antibodies against KSHV were also found more frequently in sera
from control cancer patients (22%) than in sera from blood
donors (6%). The investigators concluded that KSHV could be
associated with some other cancer types. By compiling the data from
the other studies, antibodies against KSHV were found in 20 of 447 MM
(4.5%) and 28 of 404 normal donors
(6.6%).10-12,14-17,19,21,22,32-34 When tested, the MM
patients had a normal humoral response against Epstein-Barr virus (EBV)
and cytomegalovirus (CMV),10,15,17,32-34 excluding a
generalized immune defect as responsible for the seronegativity. In
addition, patients with MGUS, who are not immunocompromised, have a
KSHV seroprevalence of only 4.5% (4/89 seropositive patients). No
serological data are currently available for the patients evaluated by
Berenson's group. In agreement with the comments given above, one
simple hypothesis to explain the lack of seroprevalence to KSHV in MM
contrary to other KSHV-related disease is that KSHV is not involved in
MM. Another hypothesis proposed by Berenson is that KSHV infected DC
and may thus, as the measle virus,35 compromise the immune
response to KSHV proteins. For this reason, we have investigated
whether functional DC were infected with KSHV.
| |
FUNCTIONAL DC ARE NOT INFECTED WITH KSHV IN MM |
The initial finding of Rettig et al suggested that DC could be a
reservoir for KSHV in MM patients, as it was shown for monocytes in
patients with KS.36 DC are essentially defined by their
unique ability to capture soluble and particulate antigens and to
present, with great efficiency, antigenic peptides to T lymphocytes,
including naive T cells.37 In Rettig et al's study, the
dendritic origin of the KSHV-infected cells was assumed only on the
basis of certain phenotypic characteristics (CD68+,
CD83+, Fascin+), but no functional assay was
performed to demonstrate it.1 CD68 is expressed by a wide
variety of cells of the dendritic/monocyte lineage. Fascin is also
expressed on B cells infected with EBV, another
herpesvirus.38 Thus, there is no evidence showing that a
putative KSHV-infected cell in MM patients is of DC origin. To generate
DC for cancer immunotherapy, two main precursor cells can be used:
CD34+ cells and monocytes. We and others were unable to
detect KSHV DNA in total apheresis cells (collected on ACD) or purified
CD34+ cells (0/33 and 0/12 positive samples,
respectively)16,18 collected after hematopoietic growth
factor and/or cyclophosphamide treatment, contrary to Berenson's data
(15/32 and 3/30 positive samples, respectively).6 We have
also shown that true functional DC (CD68+,
CD83+), generated in clinical-grade conditions from
adherent apheresis cells, were not infected with KSHV in 10 of 11 patients with MM.18 These results have been further
confirmed in four additional studies that report the absence of KSHV
DNA in DC generated either from peripheral blood adherent cells (0/17
positive samples) or from CD34+ purified cells (0/10
positive samples).16,39-41 Thus, in MM as in other cancers,
DC could be safely generated in vitro; pulsed with tumoral cell,
peptide, or RNA; and reinjected as an antitumoral cell vaccine.
| |
CONCLUSION |
In their initial reports, Berenson et al showed, using PCR and in situ
hybridization, that a majority of BM stromal cells, either generated by
in vitro culture or present in BM biopsies, were infected with
KSHV.1,2 They concluded that KSHV was present on the basis
not only of ORF26 detection, but also of the presence of ORF72, ORF65,
and ORF K2. These data lead to the attractive concept of KSHV
involvement in MM, particularly because KSHV encodes for a viral
homolog of IL-6 that is a major survival and growth factor in this
disease. Eighteen months after the initial publication, all studies
published so far fail to confirm a widespread infection of BM stromal
cells in MM patients. In addition, 14 of 15 studies showed a lack of
KSHV seroprevalence in this disease, contrary to other KSHV-related
diseases. However, confusion still exists, because in 3 studies some
amplification of the KS330 sequence related to ORF26 was confirmed from
either BM cultures or BM biopsies.11,17,21 Detection of the
KS330 sequence required very sensitive PCR, indicating that only a few
KSHV genome copies were present. These data cannot be reconciled with
the high proportion of virus-infected cells reported by Berenson's
group (2% to 10% of cells from BM biopsies and 100% of stromal
cultured cells).2 In addition, when it was investigated,
the investigators failed to amplify KSHV-related ORF other than ORF26,
despite the use of PCR with similar sensitivity. Taken as a whole,
these results emphasize that KSHV is not involved in the
physiopathology of MM.
| |
FOOTNOTES |
Submitted November 30, 1998; accepted February 10, 1999.
Address reprint requests to Bernard Klein, PhD, INSERM U475, 99 rue
Puech Villa, 34097 Montpellier Cedex 5, France.
| |
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J. Mullberg, T. Geib, T. Jostock, S. H. Hoischen, P. Vollmer, N. Voltz, D. Heinz, P. R. Galle, M. Klouche, and S. Rose-John
IL-6 Receptor Independent Stimulation of Human gp130 by Viral IL-6
J. Immunol.,
May 1, 2000;
164(9):
4672 - 4677.
[Abstract]
[Full Text]
[PDF]
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INTRODUCTION
KSHV AND BM STROMAL...