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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1506-1510
RAPID COMMUNICATION
Rapid Death of Adoptively Transferred T Cells in Acquired
Immunodeficiency Syndrome
By
Rusung Tan,
Xiaoning Xu,
Graham S. Ogg,
Pokrath Hansasuta,
Tao Dong,
Tim Rostron,
Graz Luzzi,
Christopher P. Conlon,
Gavin R. Screaton,
Andrew J. McMichael, and
Sarah Rowland-Jones
From Molecular Immunology Group, Institute of Molecular Medicine,
John Radcliffe Hospital, Oxford; Oxford Haemophilia Centre, Churchill
Hospital, Oxford; GUM, Wycombe General Hospital, High Wycombe; and
Infectious Diseases Unit, Churchill Hospital, Oxford, UK.
 |
ABSTRACT |
Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes
(CTL) probably play the major role in controlling HIV replication.
However, the value of adoptive transfer of HIV-specific CTL expanded in
vitro to HIV+ patients has been limited: this contrasts
with the success of CTL therapy in treating or preventing Epstein-Barr
virus and cytomegalovirus disease after bone marrow transplantation
(BMT). We investigated the fate of expanded HIV-specific CTL clones in
vivo following adoptive transfer to a patient with acquired
immunodeficiency syndrome (AIDS). Two autologous CTL clones specific
for HIV Gag and Pol were expanded to large numbers (>109)
in vitro and infused into an HIV-infected patient whose viral load was
rising despite antiretroviral therapy. The fate of one clone was
monitored by staining peripheral blood mononuclear cells (PBMCs) with
T-cell receptor-specific tetrameric major histocompatibility complex
(MHC)-peptide complexes. Although the CTL transfer was well tolerated,
there were no significant changes in CD4 and CD8 lymphocyte counts and
virus load. By tracking an infused clone using soluble MHC-peptide
complexes, we show that cells bearing the Gag-specific T-cell receptors
were rapidly eliminated within hours of infusion through apoptosis.
Thus, the failure of adoptively transferred HIV-specific CTL to reduce
virus load in AIDS may be due to rapid apoptosis of the infused cells,
triggered by a number of potential mechanisms. Further trials of
adoptive transfer of CTL should take into account the susceptibility of
infused cells to in vivo apoptosis.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
SEVERAL INDEPENDENT observations suggest
that cytotoxic T lymphocytes (CTL) are critical for the control of
human immunodeficiency virus (HIV) infection. Virus-specific CTL can be
detected early in HIV infection and are temporally associated with the
rapid decreases in plasma virus load after primary
infection.1,2 These early vigorous responses have been
shown to drive the selection of viruses with mutations in the targeted
epitopes, providing convincing evidence for CTL-directed
pressure.3,4 CTL responses have also been detected in
infants and sex workers with HIV exposure who remain
uninfected, suggesting that CTL could be associated with clearance or
prevention of infection in some patients.5,6 In a closely
related animal model, the inhibition of CTL by infusion of CD8-blocking
antibodies resulted in marked increases of simian immunodeficiency
virus (SIV) in the plasma and lymph nodes of infected
macaques.7 More recently, a strong inverse correlation between plasma viral load and the numbers of circulating HIV-specific CTL, measured by the novel technique of soluble peptide-HLA tetramers which represent the target of CTL recognition, has been
shown.8 Taken together, these and other reports are
consistent with the view that CTL responses are an integral part of
virus control.9
These observations raised the possibility that treating HIV-infected
patients by the adoptive transfer of CTL could be beneficial, particularly because such therapy has proved to be safe and effective for the prevention and treatment of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation in bone marrow transplant (BMT)
recipients.10-12 However, the transfer of HIV-specific CTL lines or clones in HIV-infected patients, although also safe, has so
far produced only modest results.13-15
We have transferred two autologous CTL clones specific for epitopes
derived from Gag and Pol to a patient with a high virus load and
clinical disease. To trace the fate of the infused cells in vivo, we
have used soluble major histocompatibility complex (MHC)-peptide
molecules (tetramers) specific for the T-cell receptor (TCR) of one of the infused clones.
| |
PATIENT AND METHODS |
Patient 868 is a white homosexual male (HLA-A*0201,
A*2401,B*2705,B*3501) who had been HIV+ for over 6 years
and whose clinical course included episodes of Pneumocystis
carinii pneumonia and recurrent Herpes simplex infections. At
transfer, the patient's CD4 count was 430/µL and he experienced
symptoms such as fatigue and sweats, which were attributed to a high
viral load only partially controlled by antiretroviral drugs. His
medications included zidovudine, didanosine, and prophylactic trimethoprim-sulfamethoxazole. Ethical approval was obtained from Central Oxford Regional Ethics Committee and informed consent from the patient.
HIV-specific CTL oligoclonal lines were produced by incubating fresh
peripheral blood mononuclear cells (PBMC) obtained from the patient
with irradiated, autologous EBV-transformed lymphoblastoid cell lines
(LCL) coated with peptides derived from Gag and Pol. Individual CTL
clones were established by limiting dilution. Large-scale in vitro
expansion of CTL was based on published methods.14 Cells
were grown in tissue culture flasks, each containing the clone,
irradiated allogeneic PBMC, irradiated allogeneic LCL, and anti-CD3
(OKT3, a gift from Orthoclone, Raritan, NJ). The culture
medium was RPMI-1640 supplemented with 10% human AB serum, glutamine,
penicillin, and streptomycin. Aliquots of cells and medium were sent
for microbiological testing to ensure sterility. Chromium-51 (Cr-51)
release assays were performed according to standard methods.
Anchored polymerase chain reaction (PCR) was performed as previously
described to determine the TCR of each clone and establish clonality.16,17
Synthesis of MHC-peptide tetrameric complexes has been
described.18 Purified HLA-A2 heavy chain and  2
microglobulin were synthesized using a bacterial expression system
(pET; R&D Systems, Abingdon, Oxon, UK). The heavy chain was modified by
the deletion of the transmembrane/cytosolic tail and the addition of a
C-terminal sequence containing the BirA enzymatic biotinylation site.
Heavy-chain, 2 microglobulin and peptide were refolded by dilution.
The 45-kD refolded product was isolated by fast protein liquid
chromatography (FPLC), and biotinylated by BirA.
Streptavidin-phycoerythrin conjugate (Leinco Technologies, St. Louis,
MO) was added and the tetrameric product was concentrated
to 1 mg/mL.
The CTL clones were phenotyped by dual-staining with
phycoerythrin (PE)-conjugated anti-CD8 monoclonal antibody (MoAb)
(Dako, Cambridgeshire, UK) and fluorescein isothiocyanate
(FITC)-conjugated anti-CD3 (Dako), anti-CD28 (Immunotech,
Westbrook, ME), or anti-Fas MoAb, and analyzed on a Becton Dickinson
FACScan using Cellquest software (Becton Dickinson, San Jose, CA).
Negative isotype control MoAbs were FITC- and PE-conjugated MoAbs of
irrelevant specificity (Dako). CD4 and CD8 cell counts were done in a
clinical immunology laboratory by standard methods. The plasma HIV-RNA
concentrations were determined using a commercial PCR assay (Roche
Amplicor, Branchburg, NJ).
To analyze apoptosis in vivo, PBMC were stained with 3 µL of
PE-conjugated A2 Gag-specific tetramer (1 mg/mL) and 2 µL of Tricolour-conjugated anti-CD8 (Caltag, Burlingame, CA) at 4°C for 30 minutes. After two washes the cells were stained with 100 µL
Annexin-V-Fluos (Boehringer Mannheim, Mannheim, Germany) for 15 minutes
and analyzed by flow cytometry as described above. In this study, the
gate was set on live cells, which removes more than 90% of the
necrotic cell population (data not shown).
| |
RESULTS |
HIV-specific clones.
Two HLA A*0201-restricted CTL clones derived from patient 868 were
selected for adoptive transfer. The first recognized the immunodominant
HLA-A*0201-restricted epitope from Gag p17-8, SLYNTVATL,19 and the other recognized a conserved but infrequently recognized epitope from Pol, VIYQYMDDL.20 Both the A2 Gag clone and
the A2 Pol clone expressed CD3, CD8, and Fas, but not CD28 (Fig
1A). Dual staining of the A2 Gag clone with
soluble MHC-Gag tetramer and anti-CD8 confirmed its specificity (Fig
1B), but attempts to stain clone 10 failed because of the instability
of the Pol-tetramer complex, thought to be a consequence of the low
affinity of this epitope for HLA A*0201 (data not shown). Thus, the
V and V usage and complementarity determining region 3 (CDR3) of
the clone was determined by sequencing using anchored PCR. Of 18 transcripts sequenced, all contained the same CDR3 nucleotide segment
corresponding to V22/J9.11 and V13.3/J2.3/C2 (Fig 1C),
thereby providing evidence of clonality.
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| Fig 1.
(A) Phenotype of the clones. The A2 Gag and the A2 Pol
clones were analyzed by flow cytometry. The y-axes indicate staining
with CD8-PE and the x-axes represent staining with control antibody,
 CD3-FITC, CD28-FITC, and Fas-FITC. (B) Specificity of the A2
Gag clone. The panel shows the A2 Gag clone stained with
anti-CD8-tricolor and either an irrelevant A2 tetramer- (complexed
with an EBV peptide) or A2 Gag tetramer-PE. (C) The sequences of the
CDR3 regions of the A2 pol clone T-cell receptor. The V and V
usage and CDR3 sequences of the TCR of the pol-specific CTL clone were
the same in 18 transcripts, providing evidence of clonality.
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Adoptive transfer.
The A2 Gag and Pol clones were grown to 1.1 × 109 and 1.7 × 109 cells, respectively, for adoptive transfer and the
expanded clones were shown to have maintained both HIV-specific
cytotoxic activity and an ability to suppress HIV replication in vitro
(not shown). The cells were infused into a peripheral vein over a
period of 30 minutes. The transfer was well tolerated except for a
single episode of chills and rigors within 4 to 6 hours of infusion
which rapidly subsided: the patient was subsequently well.
CD4/CD8 and virus loads postinfusion.
Table 1 shows the peripheral blood CD4 and
CD8 lymphocyte counts and the virus load before and after adoptive
transfer. Despite the substantial number of specific CTL infused, the
number of CD8+ cells had not increased at 1 hour or 20 hours after infusion, and there were no significant changes in the
virus load following therapy.
Tracking clone 19 in vivo.
PBMC obtained from the patient before and after adoptive transfer were
stained with the TCR-specific tetramer (which recognizes the TCR on the A2 Gag clone) and CD8-tricolor (Fig
2). Parallel studies were done using a
tetramer of HLA-B35 complexed with an HIV Env peptide, for which CTL
were not infused. Tetramer-positive cells accounted for 1.6% of CD8
cells in the patient before the infusion, and this increased to 2.2%
after infusion. Because 2.5 × 105 staining
events were measured at each time-point with the same reagents under
the same conditions, this represents a real and substantial increase in
tetramer-positive cells of 37%. This is close to what would be
expected assuming total body CD8+ T cells were 2 × 1011 preinfusion, so that an additional 1.1 × 109 cells were added to 3.2 × 109 preexisting
tetramer-positive cells. To determine the percentage of Gag-specific
CTL undergoing cell death, tetramer-positive cells from the patient
were costained with CD8-tricolor and a marker of apoptosis, Annexin
V-FITC (Fig 3). The
proportion of dead tetramer-positive cells showed a massive increase
from 29% before infusion to over 90% of cells 48 hours after
infusion.
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| Fig 2.
Tetramer-specific A2 Gag cells before and after infusion.
PBMC taken from the patient at the indicated timepoints were stained
with anti-CD8-tricolor, A2 Gag-specific tetramer-PE and a control, B35
Env-specific tetramer-PE. The percentages shown represent
CD8+/tetramer-positive cells.
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| Fig 3.
Death of tetramer-specific A2 Gag cells in vivo
before and after infusion. The A2 Gag clone (before infusion) and PBMC
obtained from the patient at the time-points indicated were stained
with anti-CD8-tricolor, Gag-specific tetramer-PE, and Annexin-V-FITC.
The histograms represent Annexin V staining of the
CD8+/tetramer-positive cells.
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DISCUSSION |
The utility of adoptive transfer for the treatment and prevention of
EBV and CMV infections in patients immunosuppressed after BMT11,12,21 suggested that a similar strategy might be
useful in HIV: early reports of infusion of nonspecific, autologous
CD8+ cells to HIV-infected patients showed the method to be
generally safe, although it had little impact on viral
replication.22,23 However, subsequent studies using
HIV-specific CTL lines and clones produced only modest or even
detrimental outcomes.13-15
We have taken advantage of the recently developed peptide-HLA tetramer
technology to follow the fate of a transferred CTL clone and understand
its apparent lack of in vivo efficacy. The number of cells we infused
represented close to 1% of the patient's total CD8+
cells, which is a high frequency even for HIV+ subjects and
should reasonably be expected to have a significant impact on viral
replication: however, virus load remained unchanged. We then used
fluorescently labeled, tetrameric HLA-A*0201-Gag molecules, which by
binding to the TCR of the infused clone permit specific staining of
these CTL from patient PBMC samples, to examine the survival of the
clone after infusion. There was only a short-lived increase, from a
total of 1.6% to 2.2% in the tetramer-stained CD8+ cells
after infusion. This near-40% increase at the earliest time-point
postinfusion, although substantial, is less than the predicted increase
of 62%, suggesting that some cells were eliminated or sequestered very
early. By costaining patient PBMC with anti-CD8, tetramer, and Annexin
V, we determined that the CTL were being rapidly eliminated through
apoptosis, with over 90% of tetramer-positive cells dying within 48 hours.
In mouse models, adoptive CTL transfer is effective in controlling
infection with influenza and lymphocytic choriomeningitis virus (LCMV),
and the infused cells appear both to survive and expand24-26: this is facilitated by prior depletion of
lymphocytes by irradiation, which may provide a stimulus for
repopulation of lymphoid tissue.27 Successful adoptive
transfer in humans has been limited so far to BMT recipients, whose own
immune system has been ablated and in whom cell transfer is performed
in a setting of an actively regenerating immune system: this is in
contrast to acquired immunodeficiency syndrome (AIDS) patients or
recipients of solid-organ transplants. In addition, it is often resting
spleen cells that are transferred in murine experiments, whereas we
used antigen-stimulated, cultured CTL, which may possess different characteristics because of the procedures necessary for in vitro expansion. The development of the mature, stimulated phenotype seen in
our clones, characterized by upregulation of Fas and absence of CD28
expression, may be a result of overstimulation of HIV-specific lymphocytes both in vivo (before culture) and in vitro, and may render
them particularly susceptible to premature apoptosis, particularly in
the absence of sufficient interleukin-2 (IL-2). Hamann et
al28 have previously described two populations of primed,
memory CTL and, interestingly, the CD28 subset is
dependent on exogenous cytokines such as IL-2 and IL-15 for
proliferation. While this may affect the long-term survival of infused
clones, it does not address the rapid death of the cells. The rapid
turnover of HIV-specific CTL in vivo was confirmed by our observation
that before transfer, 29% of the Gag-specific cells were undergoing
cell death. The infusion of nearly 40% more CTL did not alter the
antiviral response; instead, a higher percentage of tetramer-positive
cells underwent apoptosis after infusion, implying that a cascade of
antigen-specific cell death was triggered. Follow-up of the patient 40 days after cell transfer indicated that the number of Gag-specific CTL
had not returned to pretreatment levels (data not shown), and suggests
that the lost CTL were not replenished by expansion of naive cells.
Interestingly, a previous trial of adoptive transfer in which a single
Nef-specific clone was infused in large numbers to a patient with AIDS
showed that the clone was apparently driving the selection of viruses
containing deletions in the targeted Nef epitope.13 The
selection of escape mutants in this setting implies that the infused
CTL survived in vivo and exerted pressure on HIV-infected cells.
However, some of the cell infusions in that trial were accompanied by
very large doses of IL-2, raising the possibility that the survival of
CTL in vivo is contingent on CD4+ T-cell help, mediated
predominantly through IL-2: this is likely to be absent or
dysfunctional in HIV-infected patients. The suggestion that CTL require
proper CD4+ cell function for optimal activity is supported
by data in mice and humans. In mice with a null mutation of CD4,
infection by LCMV leads to rapid disappearance of antiviral CTL and
poor control of viral replication.29
Similarly, in immunosuppressed patients whose anti-CMV cellular
immunity was restored by adoptive transfer, CTL activity correlated
with the level of CMV-specific CD4+ T
cells.12,30 This hypothesis is also supported by recent data which show that HIV-1-specific CD4+ proliferative
responses to p24 are inversely related to viral load.31
The control of lymphocyte life span is thought to be dependent on the
regulated expression of the tumor necrosis factor (TNF)-receptor family
molecule, Fas, which induces a signal cascade leading to cellular
apoptosis upon activation by Fas ligand.32 We and others have shown that SIV and HIV-infected cells upregulate FasL, enabling them to reverse-kill antigen-specific CTL in a Fas-dependent
manner.33 We also confirmed that both infused clones showed
in vitro susceptibility to apoptosis induced by a
Fas-ligand-expressing cell line (data not shown). This may represent
another mechanism by which CTL are eliminated that probably merits
further investigation, particularly for trials of adoptive therapy for
malignancies in which Fas ligand is frequently upregulated.
Because trials of adoptive cell transfer in HIV are laborious and
infrequent, the generality of these finding will need to be confirmed
by different groups. Subsequent trials should take into account the
vulnerability of cells cultured in vitro to apoptosis and use means for
quantifying their survival in vivo. These data also suggest coinfusion
of IL-2 may increase the survival of CTL. Engineering
apoptosis-resistant antigen-specific CTL may circumvent the obstacle,
but the success of this strategy depends on better elucidating the
mechanisms of cell death in vivo.
| |
ACKNOWLEDGMENT |
We thank the patient for his generous cooperation, the Wycombe GUM
Clinic for provision of blood samples, Dr Graham Bird for CD4/CD8 flow
cytometry, and Dr S. Riddell and K. Watanabe for their very helpful
technical advice.
| |
FOOTNOTES |
Submitted July 13, 1998; accepted December 4, 1998.
R.T. and X.X. contributed equally to this work.
Supported by the UK Medical Research Council. R.T. was a Samuel
McLaughlin Fellow of Canada, and S.R.-J. is an MRC Senior Fellow.
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 Sarah Rowland-Jones, MD,
Molecular Immunology Group, Institute of Molecular Medicine, John
Radcliffe Hospital, Oxford OX3 9DS, UK.
| |
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Top
Abstract
Introduction