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Brief report
Detection of viral interleukin-6 in Kaposi sarcoma–associated
herpesvirus–linked disorders
Yoshiyasu Aoki, Robert Yarchoan, Kathleen Wyvill, Shin-ichiro Okamoto, Richard F. Little, and Giovanna Tosato
Expression of a viral interleukin-6 (vIL-6)
has been detected in certain Kaposi sarcoma (KS)–associated herpesvirus positive (KSHVⴙ) lesions. The release of vIL-6
systemically and its contribution to the
pathogenesis of HIV-related malignancies was studied. Serum vIL-6 was detected in 13 (38.2%) of 34 HIVⴙ patients
with KS, in 6 (85.7%) of 7 HIVⴙ patients
with primary effusion lymphoma (PEL)
and/or multicentric Castleman disease
(MCD), and in 18 (60.0%) of 30 HIVⴙ,
mostly homosexual, individuals without
KS, MCD, or PEL. By contrast, serum
vIL-6 was detected in only 3 (23.1%) of
13 patients with classic KS, 1 (2.5%) of
40 blood donors from the United States,
and 4 (19.0%) of 21 blood donors from
Italy. Circulating vIL-6 levels were associated with HIVⴙ status (P < .0001). However, within the HIVⴙ cohort, serum vIL-6
levels were not associated with the occurrence of KSHV-associated malignancies (P ⴝ .43). (Blood. 2001;97:2173-2176)
© 2001 by The American Society of Hematology
Introduction
Kaposi sarcoma (KS)–associated herpesvirus (KSHV; also
known as human herpesvirus 8) has been linked to 3 AIDSrelated disorders: KS, primary effusion lymphoma (PEL), and
multicentric Castleman disease (MCD).1,2 Molecular piracy of
potentially useful cellular genes has emerged as a characteristic feature of this virus.3 Viral interleukin-6 (vIL-6), produced
predominantly during lytic viral replication, exhibits approximately 25% amino acid identity to cellular IL-6.3-5 Similar to
human IL-6 (hIL-6), vIL-6 supports the growth and survival of
certain mouse and human cell lines.4-7 When expressed in
mice, recombinant vIL-6 accelerated the hematopoiesis and
induced vascular endothelial growth factor, which in turn
has been implicated in the pathogenesis of KS, MCD, and
PEL.8-12 Constitutive expression of vIL-6 has been identified in
PEL cells and in the immunoblastic cells within the mantle zone
of MCD lymph nodes.13-15 By contrast, expression of vIL-6 has
been undetectable or restricted to few lytically infected cells in
KS lesions.15,16 To investigate if vIL-6 is released into the
circulation and if, through systemic distribution, vIL-6 contributes to the development of KSHV-associated disorders, we
assayed vIL-6 in sera from HIV-infected and noninfected
individuals.
Study design
Sera from blood donors, HIV-infected individuals, and patients with KS,
PEL, or MCD were collected with consent from blood banks and clinical
centers in the United States, Italy, and Japan. Samples were stored at ⫺70°C
prior to testing.
Enzyme-linked immunosorbent assay (ELISA) for vIL-6 (assay
From the Medicine Branch and the HIV and AIDS Malignancy Branch,
National Cancer Institute, National Institutes of Health, Bethesda, MD; and
the Division of Hematology, Keio University School of Medicine, Tokyo,
Japan.
sensitivity, 30 pg/mL) was performed as described elsewhere.14 All
samples were diluted 1:10 prior to assay, and the lower limit of ELISA
sensitivity for serum vIL-6 was thus 300 pg/mL. hIL-6 was measured
using an hIL-6 Quantikine kit (R&D Systems, Minneapolis, MN) that
does not detect vIL-6.14 HIV RNA load was determined by Amplicor
HIV test (Roche Diagnostic Systems, Basel, Switzerland). Counts for
CD4⫹ and CD8⫹ cells were determined by flow cytometry. Severity of
KS in patients was assessed by both the TIS staging system17 and
counting the total number of lesions. Serum antibodies to KSHV were
detected using the whole-virus lysate ELISA kit18 (Advanced Biotechnologies, Columbia, MD) according to the manufacturer’s instructions.
All statistical analyses were performed with StatView (version 5.0.1)
software.
Results and discussion
Using a recently established vIL-6–specific ELISA that does not
detect hIL-6,14 serum vIL-6 was detected in 1 (2.5%) of 40 blood
donors from the United States (range, ⬍ 300-927 pg/mL; median,
⬍ 300 pg/mL; and 75th percentile, ⬍ 300 pg/mL) and 4 (19.0%) of
21 blood donors from Italy (range, ⬍ 300-2284 pg/mL; median,
⬍ 300 pg/mL; and 75th percentile, ⬍ 300 pg/mL) (Figure 1A). In
control experiments, all positive sera tested negative when the
plates were not coated with antibody, demonstrating that positive
reactions were not attributable to nonspecific binding (data not
shown). Immunoglobulin G (IgG) antibodies against KSHV were
detected in 4 (19.0%) of 21 Italian and 0 (0%) of 40 US blood
donors (Figure 1B).
We measured circulating vIL-6 levels in patients with classic
(HIV⫺) KS and HIV-associated KS (Figure 1A). Serum vIL-6
was detectable in 3 (23.1%) of 13 patients with classic KS
National Institutes of Health, Bldg 10 Rm 12C207, 9000 Rockville Pike,
Bethesda, MD 20892; e-mail: [email protected].
Submitted October 18, 2000; accepted November 29, 2000.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
Reprints: Yoshiyasu Aoki, Medicine Branch, National Cancer Institute,
© 2001 by The American Society of Hematology
BLOOD, 1 APRIL 2001 䡠 VOLUME 97, NUMBER 7
2173
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2174
AOKI et al
Figure 1. Detection of KSHV vIL-6 and anti-KSHV antibody in sera from blood
donors, HIVⴙ patients with or without KS, and patients with classic KS. (A) The
lower limit of ELISA sensitivity in serum samples was set at 300 pg/mL vIL-6. (B) IgG
antibody for the whole KSHV lysate was determined by ELISA. Optical density (OD)
ratios were determined by dividing the OD reading of each sample by cut-off value
(average of negative control ⫻ 3). Samples with OD ratio of at least 1.0 were
interpreted as positive. Dotted bars indicate the 75th percentile for each group.
Statistical significance of group differences was determined by the MannWhitney test.
(range, ⬍ 300-1445 pg/mL; median, ⬍ 300 pg/mL; and 75th
percentile, ⬍ 300 pg/mL) and in 13 (38.2%) of 34 HIV⫹ patients
with KS (range, ⬍ 300-7460 pg/mL; median, ⬍ 300 pg/mL; and
75th percentile, 1233 pg/mL). Compared with US blood donors,
vIL-6 levels were significantly elevated in US HIV⫹ patients
with KS (P ⬍ .0001, as measured by Mann-Whitney test), but
not in patients with classic KS (P ⫽ .86). By contrast, KSHV
antibody titers were markedly elevated in patients with both
types of KS compared with blood donors (P ⬍ .0001). To better
evaluate the results in HIV⫹ patients with KS, we measured
serum vIL-6 in 30 HIV⫹, mostly (90.6%) homosexual, individuals without clinically apparent KS, PEL, or MCD. Serum vIL-6
was detected in 18 (60.0%) of these 30 HIV⫹ individuals (range,
⬍ 300-15 060 pg/mL; median, 406 pg/mL; and 75th percentile,
1564 pg/mL). There was no significant difference in the
frequency (P ⫽ .13, Fisher exact test) and levels of vIL-6
BLOOD, 1 APRIL 2001 䡠 VOLUME 97, NUMBER 7
(P ⫽ .15, Mann-Whitney test) between these HIV⫹ patients
with KS and those without KS, PEL, or MCD. By contrast,
antibody titers to KSHV were detected more frequently in HIV⫹
patients with KS (23 [67.6%] of 34 patients) compared to those
patients without KS, PEL, or MCD (4 [13.3%] of 30 patients)
(P ⬍ .0001, Fisher exact test).
Serum samples were available from more than one timepoint in 10 of 30 HIV⫹ patients. In most cases, serum levels of
vIL-6 remained relatively stable for a period of months (Table
1). hIL-6 was undetectable or was detected at low levels (range,
⬍ 1.0-116 pg/mL, and median, 2.4 pg/mL). We evaluated
correlations between serum vIL-6 detection and a number of
parameters in HIV infection. Our analysis extended to all 64
HIV⫹ patients with (n ⫽ 34) or without (n ⫽ 30) KS, where
serum vIL-6 was either detected (n ⫽ 31) or not detected
(n ⫽ 33). There was no direct association noted between vIL-6
levels and numbers of KS lesions (P ⫽ .13, Fisher exact test
[n ⫽ 64]); KS severity by the TIS staging system17 (v ⫽ 0.307,
Cramer test [n ⫽ 64]); treatment with antiretroviral agents
(P ⬎ .99, Fisher exact test [n ⫽ 64]); or antiherpesvirus agents
(P ⫽ .27, Fisher exact test [n ⫽ 64]), HIV RNA load (P ⫽ .95,
Mann-Whitney test [n ⫽ 35]), CD4 cell counts (P ⫽ .38, MannWhitney test [n ⫽ 64]), or lymphadenopathy (P ⫽ .15, Fisher
exact test [n ⫽ 64]). These results are consistent with previous
studies showing that KSHV infects a substantial subset of
homosexual HIV⫹ patients19,20 and that KSHV replicates in only
a minority of spindle cells within KS lesions.16,21 A more recent
study demonstrated cell-free KSHV DNA in the circulation of
most HIV-1/KSHV–coinfected subjects regardless of KS disease status.22 These results further suggest that KSHV frequently replicates and expresses vIL-6 in some tissue other than
the KS lesions in KSHV-infected HIV⫹ patients.
Unlike KS lesions, hIL-6 and vIL-6 are commonly expressed in
MCD and PEL tissues.13 By immunohistochemistry, the vIL-6⫹
cells are confined to the mantle zones,13,15 whereas the hIL-6⫹ cells
are in the germinal centers.15 Additionally (Table 2), vIL-6 was
detected in 3 of 7 HIV⫹ patients with MCD and/or PEL at first
sampling (range, ⬍ 300-11 833 pg/mL). On repeated sampling, 6
(85.7%) of 7 patients had circulating vIL-6 at least once. In contrast
to KS, vIL-6 serum levels fluctuated widely in HIV⫹ patients with
MCD. This finding is consistent with recent studies showing that
KSHV load fluctuates markedly over short time periods in AIDSMCD patients,23,24 suggesting that KSHV can undergo frequent
bursts of replication in this disease. hIL-6 was detected at high
(⬎ 1000 pg/mL) levels in 3 of 11 MCD patients on at least one
occasion, but was otherwise absent or present at low levels (Table
2). There was no correlation noted between serum levels of hIL-6
and vIL-6 in this group (P ⫽ .94, Spearman rank correlation).
These results suggest that cellular IL-6 and vIL-6 are differently
regulated and perhaps play different roles in the pathogenesis
of MCD.
Overall, serum vIL-6 was detected in 46 (52.3%) of 88 serum
samples from 71 HIV⫹ patients, as opposed to 8 (10.3%) of 78
serum samples from 78 HIV⫺ individuals. Circulating vIL-6
levels were associated with HIV⫹ status (P ⬍ .0001, MannWhitney test) and the presence of anti-KSHV IgG (P ⫽ .013,
Mann-Whitney test). However, within the HIV⫹ cohort, serum
vIL-6 levels were not associated with the occurrence of
KSHV-associated malignancies (P ⫽ .43, Mann-Whitney test). In
addition to KSHV-mediated immune evasion mechanisms,25
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BLOOD, 1 APRIL 2001 䡠 VOLUME 97, NUMBER 7
KSHV vIL-6 ANTIGENEMIA
2175
Table 1. Clinical events and laboratory findings in patients with HIV infection
KS
vIL-6
pg/mL
hIL-6
pg/mL
Anti-KSHV
IgG OD
ratio*
CD4/CD8
cells/␮L
NRTI
NNRTI
PI
12/87
⫺
⬍ 300
⬍ 1.0
⬍ 1.0
19/477
AZT, ddC
—
—
—
4/88
⫹
370
60.7
⬍ 1.0
2/317
AZT
—
—
Irradiation
Case
no.
Sampling
mo/y
1
2
3
4
5
6
7
8
9
10
Antiretroviral therapy
Anti-KS
treatment
9/93
⫹
⬍ 300
3.8
5.92
242/591
AZT
—
—
—
4/99
⫹
5361
23.3
4.62
122/514
ABV
NVP
IDV
ADM
6/99
⫹
7460
⬍ 1.0
4.95
32/255
ABV
NVP
IDV
ADM
6/87
⫹
⬍ 300
⬍ 1.0
3.86
875/410
AZT
—
—
—
7/87
⫹
⬍ 300
⬍ 1.0
3.71
972/1458
AZT
—
—
—
—
5/89
⫹
⬍ 300
4.6
⬍ 1.0
441/2001
AZT
—
—
8/89
⫹
470
25.0
⬍ 1.0
502/2279
—
—
—
—
3/98
⫹
530
6.2
6.26
601/1328
AZT, 3TC
—
NFV
Thalidomide
4/99
⫹
714
3.7
6.61
714/1006
AZT, 3TC
—
NFV
IL-12
6/99
⫹
671
3.8
7.41
505/1173
AZT, 3TC
—
NFV
IL-12
8/98
⫹
⬍ 300
65.9
5.74
275/1132
D4T, 3TC
—
IDV
—
4/99
⫹
⬍ 300
⬍ 1.0
4.78
287/670
D4T, 3TC
—
IDV
Thalidomide
5/99
⫹
⬍ 300
7.6
3.32
345/782
D4T, 3TC
—
IDV
ADM
4/99
⫹
⬍ 300
⬍ 1.0
6.16
144/883
D4T, 3TC
—
NFV
—
6/99
⫹
⬍ 300
3.8
6.00
137/906
D4T, 3TC
—
NFV
ADM
4/99
⫹
4507
⬍ 1.0
4.91
260/398
AZT, 3TC
—
NFV
CDV
6/99
⫹
4753
⬍ 1.0
4.03
325/340
ABV
NVP
SQV, RTV
ADM
4/99
⫺
10 384
⬍ 1.0
5.91
441/2001
F-ddA, D4T
—
NFV
—
6/99
⫺
11 311
⬍ 1.0
5.69
502/2279
ddI, ABV
—
SQV, RTV
—
4/99
⫺
⬍ 300
⬍ 1.0
⬍ 1.0
28/936
F-ddA, D4T
—
—
—
6/99
⫺
⬍ 300
2.4
⬍ 1.0
32/1116
—
—
—
—
*OD ratios were determined by dividing the OD reading of each sample by cut-off value (average of negative control) ⫻ 3. Samples with OD ratio 1.0 were interpreted
as positive.
KS indicates Kaposi sarcoma; vIL-6, viral interleukin-6; hIL-6, human IL-6; KSHV, Kaposi sarcoma–associated herpesvirus; IgG, immunoglobulin G; OD, optical density;
NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-NRTI; PI, protease inhibitor; AZT, zidovudine; ddC, zalcitabine; ABV, abacavir; NVP, nevirapine; IDV, indinavir;
ADM, liposomed adriamycin; NFV, nelfinavir; 3TC, lamivudine; D4T, stavudine; CDV, cidofovir; SQV, saquinavir; RTV, ritonavir; F-ddA, lodenosine; ddI, didanosine.
HIV-induced immunodeficiency may allow for increased KSHV
replication and vIL-6 expression in KSHV-infected patients
with AIDS. In spite of considerable effort, the sites of initial
KSHV infection and replication and the sites of viral latency and
subsequent reactivation are incompletely characterized. Many
of the currently available serological assays for the detection of
KSHV antibodies have inadequate concordance with each
other.18,19 Thus, when suspecting KSHV infection, vIL-6 testing
may provide useful and complementary information on the
occurrence of KSHV replication.
Table 2. Human and viral interleukin-6 in sera from patients with multicentric Castleman disease and/or primary effusion lymphoma
Case
no.
HIV
status
MCD
PEL
Related
diseases
11
⫹
⫹
⫺
—
Time of
2nd/3rd
sampling
vIL-6
pg/mL
hIL-6
pg/mL
AntiKSHV
IgG OD
ratio*
—
⬍ 300
11.6
8.23
2 days later
1076
5.8
9.01
13 days later
2628
1964.4
9.63
12
⫹
⫹
⫺
KS
—
5795
⬍ 1.0
6.24
13
⫹
⫹
⫺
AIHA
—
⬍ 300
43.4
6.38
14
⫹
⫹
⫺
AIHA
—
766
6096.7
2.36
15
⫹
⫹
⫹
—
16
⫹
⫺
⫹
NHL in CNS
17
⫹
⫺
⫹
—
10 days later
2549
6432.8
2.38
—
⬍ 300
18 113.0
10.62
40 days later
17 804
134.0
—
⬍ 300
54.9
—
11 833
⬍ 1.0
448
⬍ 1.0
⬍ 300
31.7
7 months later
18
⫺
⫹
⫺
—
—
9.87
⬍ 1.0
8.49
9.73
⬍ 1.0
19
⫺
⫹
⫺
—
—
⬍ 300
38.8
⬍ 1.0
20
⫺
⫹
⫺
—
—
⬍ 300
⬍ 1.0
⬍ 1.0
21
⫺
⫹
⫺
—
—
⬍ 300
⬍ 1.0
⬍ 1.0
*Samples with OD ratio 1.0 were interpreted as positive.
MCD indicates multicentric Castleman disease; PEL, primary effusion lymphoma; AIHA, autoimmune hemolytic anemia; NHL, non-Hodgkin lymphoma; CNS, central
nervous system; for other abbreviations, see Table 1.
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2176
BLOOD, 1 APRIL 2001 䡠 VOLUME 97, NUMBER 7
AOKI et al
Acknowledgments
We thank Drs Elaine S. Jaffe and Stefania Pittaluga for reviewing lymph
node sections of MCD cases; Dr James Pluda for his assistance in caring
for the patients; Drs Michael W. Baseler, David J. Waters, and Randy A.
Stevens for coordinating the fluorescence-activated cell sorter (FACS)
and HIV RNA viral load testing; the staff of the Medicine Branch and
the HIV and AIDS Malignancy Branch, National Institutes of Health
(NIH) Clinical Center, Bethesda, MD, for their help with patients on
NIH protocols; Drs Aikichi Iwamoto, Carlo Parravicini, and James
Braun for providing serum samples; Dr Ghanshyam Gupta for his help
in statistical analysis; and Drs Yuan Chang and Patrick Moore for
helpful discussions.
References
1. Kieff E. Current perspectives on the molecular
pathogenesis of virus-induced cancers in human
immunodeficiency virus infection and acquired
immunodeficiency syndrome. J Natl Cancer Inst
Monogr. 1998;23:7-14.
2. Scadden DT. AIDS-related malignancies. Curr
Opin Oncol. 1998;10:403-404.
3. Aoki Y, Jones KD, Tosato G. Kaposi’s sarcomaassociated herpesvirus-encoded interleukin-6.
J Hematother Stem Cell Res. 2000;9:137-145.
4. Moore PS, Boshoff C, Weiss RA, Chang Y. Molecular mimicry of human cytokine and cytokine
response pathway genes by KSHV. Science.
1996;274:1739-1744.
5. Nicholas J, Ruvolo VR, Burns WH, et al. Kaposi’s
sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory
protein-1 and interleukin-6. Nat Med. 1997;3:287292.
6. Burger R, Neipel F, Fleckenstein B, et al. Human
herpesvirus type 8 interleukin-6 homologue is
functionally active on human myeloma cells.
Blood. 1998;91:1858-1863.
7. Jones KD, Aoki Y, Chang Y, Moore PS, Yarchoan
R, Tosato G. Involvement of interleukin-10 (IL-10)
and viral IL-6 in the spontaneous growth of Kaposi’s sarcoma herpesvirus-associated infected primary effusion lymphoma cells. Blood. 1999;94:
2871-2879.
10. Aoki Y, Tosato G, Nambu Y, Iwamoto A, Yarchoan
R. Detection of vascular endothelial growth factor
in AIDS-related primary effusion lymphomas.
Blood. 2000;95:1109-1110.
11. Ganju RK, Munshi N, Nair BC, Liu ZY, Gill P,
Groopman JE. Human immunodeficiency virus
tat modulates the Flk-1/KDR receptor, mitogenactivated protein kinases, and components of focal adhesion in Kaposi’s sarcoma cells. J Virol.
1998;72:6131-6137.
12. Munshi N, Groopman JE, Gill PS, Ganju RK. cSrc mediates mitogenic signals and associates
with cytoskeletal proteins upon vascular endothelial growth factor stimulation in Kaposi’s sarcoma
cells. J Immunol. 2000;164:1169-1174.
13. Staskus KA, Sun R, Miller G, et al. Cellular tropism and viral interleukin-6 expression distinguish
human herpesvirus 8 involvement in Kaposi’s
sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. J Virol. 1999;73:
4181-4187.
14. Aoki Y, Yarchoan R, Braun J, Iwamoto A, Tosato
G. Viral and cellular cytokines in AIDS-related
malignant lymphomatous effusions. Blood. 2000;
96:1599-1601.
15. Parravicini C, Corbellino M, Paulli M, et al. Expression of a virus-derived cytokine, KSHV vIL-6,
in HIV-seronegative Castleman’s disease. Am J
Pathol. 1997;151:1517-1522.
8. Aoki Y, Jaffe ES, Chang Y, et al. Angiogenesis
and hematopoiesis induced by Kaposi’s sarcomaassociated herpesvirus-encoded interleukin-6.
Blood. 1999;93:4034-4043.
16. Cannon JS, Nicholas J, Orenstein JM, et al. Heterogeneity of viral IL-6 expression in HHV-8-associated diseases. J Infect Dis. 1999;180:824828.
9. Aoki Y, Tosato G. Role of vascular endothelial
growth factor/vascular permeability factor in the
pathogenesis of Kaposi’s sarcoma-associated
herpesvirus-infected primary effusion lymphomas. Blood. 1999;94:4247-4254.
17. Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sarcoma: prospective validation of the
AIDS Clinical Trials Group staging classification.
AIDS Clinical Trials Group Oncology Committee.
J Clin Oncol. 1997;15:3085-3092.
18. Rabkin CS, Schulz TF, Whitby D, et al. Interassay
correlation of human herpesvirus 8 serologic
tests: HHV-8 Interlaboratory Collaborative Group.
J Infect Dis. 1998;178:304-309.
19. Martin JN, Ganem DE, Osmond DH, Page-Shafer
KA, Macrae D, Kedes DH. Sexual transmission
and the natural history of human herpesvirus 8
infection. N Engl J Med. 1998;338:948-954.
20. Katano H, Iwasaki T, Baba N, et al. Identification
of antigenic proteins encoded by human herpesvirus 8 and seroprevalence in the general population and among patients with and without Kaposi’s sarcoma. J Virol. 2000;74:3478-3485.
21. Zhong W, Wang H, Herndier B, Ganem D. Restricted expression of Kaposi sarcoma-associated herpesvirus (human herpesvirus 8) genes in
Kaposi sarcoma. Proc Natl Acad Sci U S A. 1996;
93:6641-6646.
22. Campbell TB, Borok M, Gwanzura L, et al. Relationship of human herpesvirus 8 peripheral blood
virus load and Kaposi’s sarcoma clinical stage.
AIDS. 2000;14:2109-2116.
23. Oksenhendler E, Carcelain G, Aoki Y, et al. High
levels of human herpesvirus 8 viral load, human
interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric
Castleman disease in HIV-infected patients.
Blood. 2000;96:2069-2073.
24. Grandadam M, Dupin N, Calvez V, et al. Exacerbations of clinical symptoms in human immunodeficiency virus type 1-infected patients with multicentric Castleman’s disease are associated with
a high increase in Kaposi’s sarcoma herpesvirus
DNA load in peripheral blood mononuclear cells.
J Infect Dis. 1997;175:1198-1201.
25. Brander C, Suscovich T, Lee Y, et al. Impaired
CTL recognition of cells latently infected with Kaposi’s sarcoma-associated herpes virus. J Immunol. 2000;165:2077-2083.
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2001 97: 2173-2176
doi:10.1182/blood.V97.7.2173
Detection of viral interleukin-6 in Kaposi sarcoma−associated herpesvirus−
linked disorders
Yoshiyasu Aoki, Robert Yarchoan, Kathleen Wyvill, Shin-ichiro Okamoto, Richard F. Little and Giovanna
Tosato
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