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Journal of Virology, July 1999, p. 6136-6140, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Identification of Human Herpesvirus 8-Specific
Cytotoxic T-Cell Responses
Mohamed
Osman,1,2
Toru
Kubo,2
Jasjit
Gill,3
Frank
Neipel,4
Marion
Becker,5
Geoffrey
Smith,5
Robin
Weiss,1
Brian
Gazzard,3
Chris
Boshoff,1,* and
Frances
Gotch2,*
Institut für Klinische und Molekulare
Virologie, Universität Erlangen-Nürnberg, D-91054 Erlangen,
Germany,4 and Department of
Genitourinary Medicine3 and Department
of Immunology,2 Chelsea and Westminster
Hospital, Imperial College School of Medicine, and
Departments of Oncology and Molecular Pathology, Royal Free
and University College Medical School, University College
London,1 London, and Dunn School of
Pathology, University of Oxford, Oxford,5 United
Kingdom
Received 28 January 1999/Accepted 26 March 1999
 |
ABSTRACT |
Human herpesvirus 8 (HHV-8) (or Kaposi's sarcoma-associated
herpesvirus) is implicated in the etiopathogenesis of Kaposi's sarcoma
(KS) and certain lymphoproliferations. The introduction of more
effective therapies to treat human immunodeficiency virus infection has
led to a decline in the incidence of KS and also in the resolution of
KS in those already affected. This suggests that cellular immune
responses including cytotoxic T lymphocytes (CTLs) could play a vital
role in the control of HHV-8 infection and in KS pathogenesis. Here we
elucidate HLA class I-restricted, HHV-8-specific cellular immune
responses that could be important in the control of HHV-8 infection and
subsequent tumor development. We show the presence of CTLs against
HHV-8 latent (K12), lytic (K8.1), and highly variable (K1) proteins in
infected individuals.
| |
TEXT |
The interface between infection,
immunity, and malignancy is highlighted by cancers prevalent in
patients infected with human immunodeficiency virus (HIV) and in organ
transplant recipients. Immunosuppressed individuals are prone to tumors
caused by the gamma herpesviruses Epstein-Barr virus (EBV) in lymphomas
(25) and human herpesvirus 8 (HHV-8; also called Kaposi's
sarcoma-associated herpesvirus) in Kaposi's sarcoma (KS) and certain
lymphoproliferations (2, 7, 11).
HHV-8 is the most recently identified oncogenic virus and is causally
linked to KS (6, 10), the most common tumor in HIV-infected individuals, and also to primary effusion lymphoma and
the immunoblastic variant of Castleman's disease (4, 8, 29). The introduction of aggressive anti-HIV therapies has led to
a decline in the incidence of KS in AIDS patients and also in the
resolution of KS in those already affected (16). This suggests that cellular immune responses, compromised in AIDS but recovering after highly active antiretroviral therapy (HAART), could be important in the control of HHV-8 infection and in the development of KS.
The immune system is capable of mounting potent attacks on invading
viruses and of eliminating some viral infections. Virus-specific, HLA-restricted cytotoxic T-lymphocyte (CTL) responses are critical to
clear early viremia in acute HIV infection, are important in the
control of opportunistic viral infections such as cytomegalovirus or
herpes zoster reactivation, and play an important role in the control
of human papillomavirus-induced squamous cell carcinomas and in
EBV-induced lymphoproliferation.
We postulate that HHV-8 establishes a persistent infection, which
is normally controlled by the immune system, and that the number of
HHV-8-infected cells is under immunological control. When
this immune control declines due to acquired or iatrogenic immunosuppression, the number of HHV-8-infected cells increases with the subsequent unchecked proliferation of virally infected cells
and the development of HHV-8-related tumors. The human gamma herpesviruses EBV and HHV-8 establish latent infections in lymphoid cells, where the viral episomes express only a limited number of genes
(the so-called latent genes), and this means that only a limited
number of peptides may be recognized in association with HLA class I
molecules by CTLs. In EBV infection, virus-specific CTL
activity directed against peptides from latent and lytic
proteins is important in the pathogenesis of
EBV-associated diseases (26).
To investigate the existence of CTLs against HHV-8, we selected the
products of three HHV-8 open reading frames: K1, K8.1, and K12.
None of these have sequence similarity to EBV proteins, thereby
excluding the possibility of cross-reactivity with EBV-specific CTLs.
K1 is at the left-hand side end of the HHV-8 genome, in a position
equivalent to the gene encoding the herpesvirus saimiri transforming
protein (STP), but K1 has no sequence or structural similarity to STP.
K1 is oncogenic when overexpressed in rodent fibroblasts
(19); however, it is not yet clear whether this protein is
expressed in latency in mesenchymal cells (e.g., KS spindle or tumor
cells). In effusion lymphoma cells K1 expression is restricted to the
lytic cycle (18). K1 is highly variable among HHV-8
isolates (22) and is therefore presumed to be under significant biological pressure, suggesting that this protein may be
important in HHV-8 pathogenesis.
K8.1 is a 228-amino-acid viral glycoprotein expressed during lytic
viral replication (20, 24). K8.1 is highly immunogenic and
therefore useful to measure humoral immunity against HHV-8 (24). K8.1 has no overt amino acid sequence similarity with any viral or cellular sequence currently available in databases (24). K8.1 localizes on the surfaces of cells and virions
(20). The open reading frame in EBV that shares genomic
position and orientation with K8.1 encodes gp350/220, which is known to
bind to CR2 (CD21) on host cells (32). This suggests that
K8.1 might also be involved in cell attachment (20).
gp350/220 of EBV evokes powerful cellular immune responses and is
indeed being investigated as an EBV vaccine (9, 25).
K12 encodes a unique viral protein expressed during latent infection
(35). K12 is expressed in nearly all KS spindle cells and
also in latently infected primary effusion lymphoma cells (30). K12 is transforming in vitro (21), and it
may therefore play a role in HHV-8-induced cellular proliferation.
Study participants.
Study participants were selected from
HIV-positive and -negative individuals attending the Genitourinary
Clinic at the Kobler Centre, Chelsea and Westminster Hospital, London,
United Kingdom. Control donors were laboratory workers who were at a
low risk of HHV-8 infection. The study was approved by the ethical
committee of the Chelsea and Westminster Hospital Trust.
HLA typing.
DNA was extracted from 200 µl of EDTA-peripheral
blood, by using a QIAamp blood kit (Qiagen, Crawley, United Kingdom).
HLA class I typing was performed by amplification of refractory
mutation system PCR with sequence-specific primers (17). PCR
was performed in 96-well PCR plates with 5 to 20 µg of DNA, 5 µl of
allele sequence-specific primers (Oxford Transplant Centre, Oxford,
United Kingdom), deoxynucleoside triphosphates, and Taq DNA
polymerase. Products were visualized in a 1% agarose gel with ethidium bromide.
HHV-8 serological assay.
HHV-8 antibodies were
detected by using an indirect immunofluorescence serological assay as
described previously (12, 34). To determine anti-HHV-8
antibody titers, sera were diluted in 3% fetal calf serum in
phosphate-buffered saline. Twofold dilutions were made starting at a
concentration of 1:100.
Construction of recombinant modified vaccine Ankara (MVA)
expressing K1, K8.1, and K12.
Total cellular DNA was extracted
from the primary effusion lymphoma cell line BCP-1, which carries
HHV-8 but not EBV (1, 12). The K1 open reading
frame was amplified from BCP-1 DNA by PCR with the forward primer
5'-GGACGCGGCCGCGTCTTTCAGACCTTGTTGGAC-3' and the
reverse primer
5'-AATCCAGCGGCCGCGAATGTCAGTACCAATCCAC-3'. The K1 PCR product was digested with NotI
restriction endonucleases (NotI restriction sites are
underlined), the staggered ends were filled in with the Klenow fragment
of DNA polymerase, and the blunt-ended fragments were inserted into the
SmaI site of pSC11 (5).
The K12 open reading frame was amplified from BCP-1 DNA by PCR with the
forward primer
5'-GCATGCGGCCGCATGGATAGAGGCTTAACGG-3' and
the reverse primer
5'-CGTAGCGGCCGCTAGCTTCAGTGCGCGC-3'. The K12 PCR
product was digested with NotI restriction endonucleases (NotI restriction site is underlined) and inserted into a
novel NotI site of pCS11. This NotI site in the
pSC11 plasmid was created by ligating a synthetic oligonucleotide
linker containing it to the SmaI-digested pSC11. The new
version of the plasmid was called pSC11N.
The K8.1 open reading frame was excised from plasmid pCDNA-K8.1
(24) with BamHI and XbaI restriction
endonucleases, the staggered ends were filled in with the Klenow
fragment of DNA polymerase, and the NotI linker was ligated.
The resulting K8.1-NotI was digested with NotI
and inserted into the NotI site of pSC11N.
BHK21 cells were infected with MVA at 0.05 PFU per cell. pSC11 or
pSC11N plasmids carrying K1, K8.1, or K12 genes were transfected
with
Perfect Lipid (Invitrogen, Groningen, The Netherlands). Total
virus
from the cells and supernatant were harvested 3 days later
and used for
the reinfection of BHK21 cultures. The plaques of
recombinant MVAs
(rMVAs) were identified by using X-Gal
(5-bromo-4-chloro-3-indolyl-
-
D-galactopyranoside)
color
selection (
3) and purified by five rounds of plaque
purification.
Bulk stocks of the rMVAs were grown and purified by the
centrifugation
of cytoplasmic extracts through a 36% (wt/vol) sucrose
cushion
in a Beckman SW28 rotor at 13,500 rpm for 80 min. rMVA
expressing
Escherichia coli -galactosidase was used as a
control.
Cell monolayers were grown to approximately 70% confluency and
infected with different rMVAs. Cells were harvested 16 h later,
washed with phosphate-buffered saline, and resuspended in a lysis
buffer for RNA
extraction.
RT-PCR.
Total RNA was extracted from individual rMVA-infected
cells by using an RNeasy kit according to the manufacturer's
instructions (Qiagen). For reverse transcription (RT)-PCR the
Stratagene RT-PCR kit was used according to the manufacturer's
instructions. RT of 5 µg of total RNA was performed at 37°C for
1 h in a 50-µl reaction mixture containing 300 ng of random
primers, 0.2 mM concentrations of deoxynucleoside triphosphates, and 50 U of Moloney murine leukemia virus reverse transcriptase. Subsequently
the above-mentioned mixture was heated to 90°C for 5 min. Five
microliters of the RT product was subjected to PCR amplification with
sequence-specific primers for each gene. Amplification was done for 30 cycles (94°C for 30 s, 55°C for 30 s, and 72°C for
45 s) and a final cycle at 72°C for 10 min. K8.1 was
amplified with the forward primer 5'-ATGAGTTCCACACAGATTCGC-3'
and the reverse primer 5'-CACTATGTAGGGTTTCTTACGCCG-3'. The sequences of the primers for K1 and K12 are described above.
CTL assays.
Peripheral blood mononuclear cells were isolated
on a Ficoll-Hypaque density gradient and washed twice in RPMI 1640 (Sigma). Peripheral blood mononuclear cells were then cultured at a
density of 1 × 106 to 2 × 106/ml in a
24-well plate (Nunc) at 37°C in 5% CO2, together with a
sonicated preparation of rMVA expressing K1, K8.1, or K12 in RPMI 1640 supplemented with 10% fetal calf serum (R10). rMVAs were used at a
multiplicity of infection of 0.2. The cultures were supplemented with
10 U of recombinant human interleukin 2 per ml on day 3 and were tested
for specific killing by CTLs on days 10 to 14.
Virus-infected target cells were prepared by incubating pelleted
autologous EBV-transformed B-cell lines (BCLs) or HLA-matched
or -mismatched BCLs (kindly provided by Alan Rickinson,
University
of Birmingham, Birmingham, United Kingdom) with rMVA
K1, rMVA
K 8.1, rMVA K12, or rMVA
-galactosidase at a multiplicity
of
infection of 10 in a conical-bottom tube for 90 min. Target cells
were then washed, resuspended in R10, and cultured overnight to
allow the expression of viral genes. Target cells were labelled
with
150 µCi of
51Cr/10
6 cells (Amersham
International, Little Chalfont, United Kingdom)
for 1 h
before being washed three times and plated into U-bottom
96-well plates
at a density of 5 × 10
3 cells/well in 100 µl.
Effectors were added at different concentrations
in 100 µl of R10,
and the mixtures were incubated for 4 h. All
assays were performed
in duplicate. A total of 20 µl of the supernatant
was removed from
each well onto a filter mat (Wallac), which was
dried and then sealed
with a plastic bag containing a liquid scintillation
cocktail (Wallac).
The amount of
51Cr was counted on a Wallac counter. The
percentage of specific
lysis was calculated by using the following
formula: 100 × (
E
M)/(
TM),
where
E is
the amount of
51Cr released into 20 µl of supernatant
from wells containing targets
and effectors,
M is the amount
of
51Cr released into wells containing targets and the
medium only,
and
T is the amount of
51Cr
released from wells containing targets lysed by the addition
of 5%
Triton X-100. The amount of spontaneous release [100 × (
M/
T)]
was always less than 35%. A positive CTL response
was defined
as one in which the specific lysis of target cells was more
than
10% above that of the same target cell infected with
-galactosidase-expressing
rMVA (
13,
14).
HLA class I blocking assay.
In the inhibition experiments, the
monoclonal antibody W6/32 (Dako), specific for HLA class 1-peptide
complexes, was added to the target cells 30 min prior to coincubation
with the effector cells. The final concentration of antibody was
1 µg/ml (23). The HLA typing, HIV and HHV-8
serological status, HHV-8 antibody titer, CD4+ T-cell
count, and clinical status of all patients and donors are presented in
Table 1.
The lack of antibodies against K1, K8.1, and K12 hindered our ability
to assess their expression at the protein level. The
expression of rMVA
K1, K8.1, and K12 was therefore assessed by
RT-PCR. Following the
infection of BHK21 cells, all three genes
were amplified by RT-PCR with
sequence-specific primers (Fig.
1); K1
migrated at 911 bp, K8.1 migrated at 790 bp, and K12 migrated
at 190 bp, corresponding to the predicted molecular sizes.
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FIG. 1.
RT-PCR results showing RNA transcripts for rMVA K1,
K8.1, and K12 from BHK21 cells. The amplification was done in the
presence (+) or absence () of reverse transcriptase. The band sizes
for K8.1 are in agreement with the sliced products ( and ) of
this transcript.
|
|
Twenty individuals (six who were HHV-8
+ and
KS
+, seven who were HHV-8
+ and
KS
, and seven who were HHV-8
) were
evaluated for HHV-8-specific CTLs, by using rMVA (K1, K8.1,
and
K12) and control rMVA
-galactosidase-infected target cells
(Table
1). The lymphocytes were prestimulated as detailed above
and used as
effectors in a
51Cr release
assay.
One hundred percent of HHV-8
+ KS
patients
had CTL responses to K1, K8.1, or K12 (Table
1 and Fig.
2); K1, K8.1, and K12 were
recognized by
the immune systems of three, four, and five patients,
respectively.
Among the HHV-8
+ KS
+ patients, the CTL
response rate was 33% (two of six patients).
Patient 6 recognized K8.1
only weakly (12% lysis). Patient 5,
who had very mild KS, recognized
K8.1 and K12 (12 and 21%). Patient
8, who previously had KS that
resolved during HAART, showed a
CTL response to K12. Of note, K1 was
not recognized by any of
the patients with KS. None of the
HHV-8 immunofluorescent antibody-negative
patients had
HHV-8-specific CTL responses. No lysis of control
targets
infected with rMVA expressing
-galactosidase or of HLA-mismatched
target cells infected with rMVA was seen.
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|
FIG. 2.
Recognition of rMVA-expressed HHV-8 antigens by CTLs
from an HHV-8+ KS patient (no. 3), an
HHV-8+ patient without KS (no. 11), and an HHV-8
negative patient (no. 17). Patient details are shown in Table 1.
CTLs tested at the effector-to-target ratios of 40:1 and 10:1 are
shown. b-gal, -galactosidase.
|
|
To evaluate whether the lysis observed was HLA class I restricted, CTL
lines, obtained from patients 6, 13, and 15 and directed
against K8.1,
K12, and K1, respectively, were analyzed in the
presence or absence of
anti-HLA class I (W6/32) antibody. Lytic
activity was completely
inhibited at an effector/target ratio
of 40:1 (Fig.
3) when target cells were pretreated with
the anti-HLA
class I antibody.
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FIG. 3.
Inhibition of CTL activity by treatment with anti-HLA
class I antibody (W6/32). The targets were preincubated for 30 min at
22°C before the addition of effector cells at a concentration of
40:1.
|
|
Conclusions.
We demonstrate here that HHV-8, like other
herpesviruses, is able to elicit HLA class I-restricted CTL responses.
We show specific responses for three different HHV-8
proteins
K1, K8.1, and K12, which had been introduced into MVA.
The CTL activity against these HHV-8 proteins is HLA class I
restricted, implying that they represent CD8+ T cells.
A cellular immune response against both HHV-8 latent (K12) and
lytic (K8.1) proteins is shown. CTLs against EBV lytic proteins
appear
to be important in the pathogenesis of EBV replicative
lesions
(
31) and could be important in viral replication and
also
viral shedding. CTLs against latent proteins could be essential
to
prevent the outgrowth of virally transformed
cells.
The relative structure and position of HHV-8 open reading frame K1
is comparable with the latent membrane protein of EBV and
herpesvirus
saimiri STP. It appears that K1 has been under significant
biological
pressure and is used to distinguish four major clades
(A, B, C, and D)
of HHV-8 that are associated with different ethnic
groups in
different geographical settings (
15). CTL activity
against
this protein might therefore be important in HHV-8 transmission
and
pathogenesis in different geographical regions. The K1 sequence
used in
this study was cloned from BCP-1 cells (
1) and belongs
to
the A clade of HHV-8, which is frequently seen in AIDS-KS patients
in the West (
15). The absence of CTLs against K1 in some
individuals
could be due to infection with different HHV-8 strains.
We are
presently using overlapping peptides from the different K1
isolates
to delineate K1-specific CTL responses in
HHV-8
+ patients from different ethnic
groups.
CTLs restricted by the HLA molecules A2, A3, B7, and B8 were all shown
to recognize at least one of the HHV-8 proteins tested.
HLA alleles
were found to present epitopes from more than one
viral protein (e.g.,
HLA A2- and A3-restricted epitopes were demonstrated
in K8.1
and K12, and HLA B8 presented all three proteins). This
suggests a
broad repertoire of CTL responses to HHV-8 as seen
in other viral
infections. HLA A2, A3, B7, and B8 are present
in more than 60% of the
Caucasian population, and it should therefore
be possible to identify
and study HHV-8-specific CTLs by using
these constructs in many
individuals.
Although this is a pilot study, we were able to compare patients with
and without KS; we did not demonstrate HHV-8-specific
CTL responses
in most patients with KS, indicating that a decline
in cellular immune
responses against HHV-8 may be present in HIV
+ patients
with KS and could contribute to KS pathogenesis. This
would be
reminiscent of the lack of EBV-specific CTLs seen in
immunosuppressed patients, which correlates with the onset of
EBV-driven lymphoproliferation (
25,
27). One patient
(patient
8) previously had KS, but this resolved during HAART, and we
were
able to demonstrate CTLs specific to the K12 protein in this
patient.
No HHV-8-specific CTL responses were seen in HHV-8
antibody-negative
patients, and no responses were seen to HLA-matched
or autologous
target cells infected with control MVA containing
-galactosidase.
Overall, we were less likely to see CTL responses in
patients
with a high antibody titer against HHV-8. Antibody titer
correlates
with viral load (
28,
33). This therefore suggests
that the
lack of CTL activity correlates with a higher HHV-8 viral
load,
although we will need a higher number of patients to confirm
this.
KS is a complex tumor, and various immune responses could be involved
in its pathogenesis (
10). The rapid resolution of
KS in some
HIV-positive patients started on HAART suggests that
a small
improvement in immunity might be important in disease
control.
CD4
+ T-helper responses, not studied here, natural killer
cells, and
leukocyte-activated killer cells could also be involved in
the
control of the growth of HHV-8-positive cells. The rapid
decline
in the viral load of HIV itself has also been suggested to play
a role in the response of KS lesions to HAART (
10).
The identification of HLA class I-restricted CTLs against
HHV-8 will allow us to identify viral epitopes that serve as
recognition
sites for HHV-8-specific CTLs and to evaluate the
effectiveness
of HAART in the reconstitution of HHV-8-specific
CTLs. We are
currently conducting a prospective study to
evaluate the effects
of HAART on HHV-8-specific CTL
responses.
| |
ACKNOWLEDGMENTS |
This work was supported by the U.K. Medical Research Council and
The Cancer Research Campaign. Chris Boshoff is a Glaxo Wellcome Prize Fellow.
We thank Dimitra Bourboulia for providing the figures and Nesrina Imami
for technical help.
| |
FOOTNOTES |
*
Corresponding author. Mailing address for Chris
Boshoff: Department of Oncology, 91 Riding House St., University
College London, London W1P 6BT, United Kingdom. Phone: 44-171-504-9557. Fax: 44-171-504-9555. E-mail: c.boshoff{at}ucl.ac.uk.
Mailing address for Frances Gotch: Department of Immunology, Chelsea
and Westminster Hospital, London SW10 9NH, United Kingdom. Phone:
44-181-746-8257. Fax: 44-181-746-5997. E-mail:
f.gotch{at}ic.ac.uk.
| |
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Journal of Virology, July 1999, p. 6136-6140, Vol. 73, No. 7
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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