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Journal of Virology, August 2000, p. 7678-7682, Vol. 74, No. 16
Départements de Biologie Clinique ou de
Médecine, Institut Gustave Roussy, 94805 Villejuif,1 Laboratoire
d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM U445,
Institut Cochin de Génétique Moléculaire,
Université R. Descartes, Hôpital Cochin, 75014 Paris,2 Transgène S.A., 67000 Strasbourg,3 and Laboratoire de
Virologie et Pathogénèse Virale, CNRS UMR 5537,
Faculté de Médecine RTH Laennec, 69008 Lyon,4 France
Received 30 March 2000/Accepted 17 May 2000
We previously demonstrated that a single injection of
109 PFU of recombinant adenovirus into patients induces
strong vector-specific immune responses (H. Gahéry-Ségard,
V. Molinier-Frenkel, C. Le Boulaire, P. Saulnier, P. Opolon, R. Lengagne, E. Gautier, A. Le Cesne, L. Zitvogel, A. Venet, C. Schatz, M. Courtney, T. Le Chevalier, T. Tursz, J.-G. Guillet, and F. Farace,
J. Clin. Investig. 100:2218-2226, 1997). In the present study we
analyzed the mechanism of vector recognition by cytotoxic T lymphocytes (CTL). CD8+ CTL lines were derived from two patients and
maintained in long-term cultures. Target cell infections with
E1-deleted and E1-plus E2-deleted adenoviruses, as well as
transcription-blocking experiments with actinomycin D, revealed that
host T-cell recognition did not require viral gene transcription.
Target cells treated with brefeldin A were not lysed, indicating that
viral input protein-derived peptides are associated with HLA class I
molecules. Using recombinant capsid component-loaded targets, we
observed that the three major proteins could be recognized. These
results raise the question of the use of multideleted adenoviruses for
gene therapy in the quest to diminish antivector CTL responses.
Replication-deficient recombinant
adenoviruses are being studied widely as therapeutic gene transfer
vectors (4, 11, 20, 21, 24, 25, 27, 34). Despite unique
advantages, the major limitation of these vectors is the host antiviral
immune response, which causes transitory transgene expression in vivo as well as inefficient gene transfer when rechallenged (17, 28-32). In humans, natural infection induces neutralizing
antibodies, which were recently correlated with the response elicited
by vector administration (12) and may directly impair viral
attachment and penetration (8). Cellular cytotoxic responses
to the virus and to the transgenic protein were found to be responsible
for the destruction of transduced cells and thus for a dramatic
reduction in viral genome persistence (17, 26, 28, 30). The
first studies with E1-deleted vectors in rodents suggested that de
novo-synthesized antigens played a major role in inducing antiviral
cytotoxic T lymphocytes (CTL) (31). Indeed, despite the
deletion of the E1 region, first-generation vectors continued to
express low levels of early and late viral genes. Additional deletions
that inactivated E2A or E4 regulatory genes were therefore introduced
to reduce such expression. In vivo testing of second-generation vectors showed no diminution in the antiviral immune responses and no improvement of viral genome persistence (15). However, in
the absence of a transgene, antiadenovirus CTLs did not appear to be
effective in eliminating the transduced cells (15).
Transgene expression induced by E1-plus E4-deleted vectors in
immunodeficient or recombinant protein transgenic models was also
transient, suggesting a critical role for E4 products in the regulation
of transgene transcription (1, 3, 6), which was recently
confirmed (16). Overall, studies have revealed that the
immune mechanism elicited by these vectors is extremely complex. It is
noteworthy that its impact on the efficacy of gene transfer in humans
remains poorly understood. Its elucidation is nonetheless essential to further improve gene therapy protocols.
We previously reported the analysis of humoral and cellular immune
responses to the vector and the Antiadenovirus CD8+ CTL lines were derived from
postinjection peripheral blood mononuclear cells obtained from two
patients and expanded in long-term cultures. After 5 to 7 days of
stimulation with adenovirus (9), the cells were tested for
antiadenovirus cytotoxic activity in a 4-h standard chromium release
assay (data not shown). Non-CD4+ and non-CD56+
cells were then negatively selected by immunorosetting, and the CD8+ TcR The autologous LCL was used in cytotoxicity assays. Since this cell
line is poorly permissive to adenovirus, we first determined the viral
dose and the infection duration required for optimal sensitization by
first-generation vectors. A 24- or 18-h infection was sufficient to
sensitize LCL targets, but optimal recognition was obtained only after
a 40-h infection (data not shown). The minimal infectious dose was
about 600 to 1,000 particles per cell (10 to 13 PFU/cell) with Ad-CFTR
(first-generation adenovirus carrying the CFTR gene) and AdE1°
(first-generation adenovirus without a transgene), showing that the
infectivities of two first-generation adenovirus vectors were similar
in a semipermissive cell line (data not shown). Particle number were
determined following lysis of the viral suspension by measuring optical
density (as described in reference 16). All the
experiments reported in this paper were calibrated in particles per
cell, since this is a more accurate reflection of the amount of
exogenous viral protein provided by the infection.
Viral protein expression is markedly reduced or even undetectable in
cells infected with second-generation adenovirus vectors (with E1 plus
E2 deleted or with E1 plus E4 deleted) compared to that in cells
infected with first-generation vectors (E1 deleted) (15). In
our study, target cells were infected at a multiplicity of infection
(MOI) of 20,000 particles/cell with two isogenic vectors without a
transgene (AdE1° and AdE1E2°) and differing only in the E2A
deletion. The transcription of early (DNA binding protein) and late
(structural proteins) viral antigens was assessed by Northern blot
analysis. Despite the high MOI, no viral RNA was detected in either
first- or second-generation-vector-infected LCL. Northern blot results
obtained by using a probe for the fiber are shown in Fig.
1A. Nevertheless, adenovirus-specific
CTLs recognized AdE1°E2°- as well as AdE1°-infected target cells
(Fig. 1B), supporting the hypothesis that input viral proteins are
recognized by CTLs. This experiment, as well as others described in
this report, was successfully repeated at least twice with CTLs from
the two patients. However, surprised that Northern blot analysis
yielded similar results for first- and second-generation
adenoviruses, we decided to further test our findings by using
actinomycin D (Act-D), a fungal metabolite, to inhibit RNA
transcription. Target cells were treated with Act-D for 30 min before
being infected and throughout the chromium release assay, to prevent de
novo viral protein synthesis. The transcription block was controlled by
[3H]uridine incorporation. Target cells were infected
with 12,000 particles of Ad-CFTR per cell for 24 h and were either
treated or not treated with Act-D (5 µg/ml before infection, 0.2 µg/ml during and after infection) in parallel with uridine
incorporation. As shown in Fig. 2, CTLs
lysed Act-D-treated targets as efficiently as they lysed untreated
targets whereas uridine incorporation was completely abrogated in
Act-D-treated targets. This result confirmed that de novo viral gene
transcription is not required for CTL recognition of infected cells.
This finding is consistent with a recent report on mice which showed
that inactivated adenovirus-infected cells are efficiently recognized
by CTLs (14).
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Immune Response to Recombinant Adenovirus in Humans: Capsid
Components from Viral Input Are Targets for Vector-Specific
Cytotoxic T Lymphocytes
ABSTRACT
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-galactosidase protein in patients
with lung cancer who received a single intratumor injection of an
E1-deleted recombinant adenovirus encoding the lacZ gene
(9, 27). We observed that a strong in vivo vector-specific cytotoxic response was induced by a 109 PFU injection. In
the present study, we evaluated the respective contributions of de
novo-synthesized antigens and viral input antigens in the CTL response
and identified the target proteins recognized in two patients. The
results revealed the mechanisms of adenovirus recognition by CTL and
have important implications for the use of additionally deleted vectors
aimed at diminishing anti-vector-specific responses in gene therapy protocols.
+ phenotype was verified by flow
cytometry (data not shown). The CTLs were then expanded on
adenovirus-infected irradiated feeder cells composed of autologous
Epstein-Barr virus-immortalized lymphoblastoid cell lines (LCL)
(obtained as described in reference 9) and maintained for 2 to 3 weeks. All the CTL lines tested in subsequent experiments displayed 76 to 506 lytic units at 20% lysis of 5 × 103 adenovirus-infected targets per 107 effectors.
View larger version (22K):
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FIG. 1.
(A) Northern blot analysis of LCL infected with first-
and second-generation vectors. LCL were infected with 20,000 particles
of AdE1° (E1 deleted), AdE1E2° (E1 and E2 deleted), or AdE1E4°
(E1 and E4 deleted) per cell and 10 PFU of Vac-Fi (recombinant vaccinia
virus encoding the adenovirus type 5 fiber) per cell as previously
described (9). 293 cells infected with wild-type adenovirus
were used as positive controls. All these viruses were produced by
Transgene SA. Adenovirus vector construction was described in reference
15. Total RNA was extracted 60 h postinfection
for adenovirus vectors and 24 h for Vac-Fi (the delay was used to
obtain maximal transcription). RNA (10 µg) was separated on a
formaldehyde-agarose gel, transferred to a nitrocellulose membrane, and
probed for the fiber with a 32P-labeled fragment of the
fiber sequence. (B) CTL recognition of first- and second-generation
adenovirus vectors. CTL were assayed in the presence of LCL infected
40 h prior to the test with 20,000 particles of AdE1° or
AdE1E2° per cell, or mock infected, in a standard 4-h chromium
release assay.
View larger version (20K):
[in a new window]
FIG. 2.
Effect of the viral gene transcription block on CTL
lysis. (A) LCL treated with Act-D (5 µg/ml) 30 min prior to and
during infection or left untreated were infected for 1 h with
12,000 particles of Ad-CFTR per cell and then resuspended in 5 ml of
complete medium with or without 0.2 µg of Act-D per ml. After 24 h of culture, CTL recognition was assayed on autologous mock- or
adenovirus-infected Act-D-treated and untreated targets in a standard
4-h chromium release assay (a concentration of 0.2 µg of Act-D per ml
was maintained throughout the test). (B) In parallel,
adenovirus-infected 51Cr-labeled targets were seeded in
triplicate in 96-well plates (1.5 × 105 cells/well)
and RNA transcription was measured by [3H]uridine (1 µCi/well) incorporation after 18 h of culture. E:T,
effector-to-target-cell ratio.
Viral inoculum structural-antigen recognition by human CTLs has been
documented with naturally occurring cytomegalovirus and influenza virus
infections (19, 33). However, the mechanisms of exogenous
protein processing via the class I major histocompatibility complex
(MHC) pathway are poorly understood (10). Brefeldin A (BFA)
disrupts intracellular membrane traffic by disassembling the Golgi
complex, thereby preventing the presentation of intracellularly processed MHC-peptide complexes, whereas complexes already present on
the cell surface are not affected by the drug. In our study, target
cells were treated by BFA (1 µg/ml) before and during infection (with
1,000 particles of Ad-CFTR or AdE1° per cell for 18 h). A low
MOI and a short infection duration were used to facilitate the effect
of the drug. In spite of suboptimal conditions, significant lysis of
infected cells was achieved, and this was totally blocked by BFA
treatment (Fig. 3). In addition, patient
1 CTLs (HLA A2 A23 B44 B49 C7 C8) were tested against an homozygous
allogeneic LCL (HLA A2 B60 C10), mismatched for all patient 1 class I
HLA restrictions except for HLA A2. For two effector-to-target-cell ratios, the specific lysis against the allogeneic target represented 40% of that obtained against the autologous target (data not shown). Therefore, approximately 40% of Ad-specific lytic activity was mediated by HLA A2-restricted CTLs. Together, these results suggest that CTLs recognize class I MHC peptide complexes resulting from intracellular processing. Internalized virion capsid proteins are
therefore processed inside adenovirus-infected cells and serve as a
source of peptides for class I MHC molecules.
|
To determine capsid component recognition by CTLs, recombinant
adenovirus type 5 hexons (Hx), penton bases (Pb), and fibers (Fi) were
produced upon lysis (by successive freezing and thawing) of Sf9 cells
infected with recombinant baculoviruses, as previously described
(8), and used in gamma interferon (IFN-
) enzyme-linked immunospot (ELISPOT) assays. The rationale for using ELISPOT instead of
the lysis assay was twofold: (i) assuming that adenovirus-specific lytic activity would be distributed among the three capsid components, we selected the ELISPOT technique, which demonstrated higher
sensitivity, and (ii) these experiments were considerably limited by
the quantities of CTLs that could be derived from few patient blood
samples (ELISPOT required threefold fewer CTL than the chromium release
assay did). Recombinant protein extracts were introduced into LCL by
hypertonic loading lasting 10 min (18). After 12 h of
incubation, cells were used as targets (5,000 cells/well) in an IFN-
ELISPOT assay (5) at effector-to-target-cell ratios ranging
from 15:1 to 1:1. As shown in Fig. 4A,
IFN--secreting CTLs from patient 1 were visualized, indicating
recognition of recombinant Hx- and Fi-loaded targets but not Pb-loaded
targets. In contrast, Pb-loaded cells were targets for CTLs from
patient 2 whereas Hx- and Fi-loaded cells were not (Fig. 4B). These
results are in agreement with those of a recent study of mice which
demonstrated that the CTL response to both adenovirus capsid components
and the transgene product varied among mouse strains, indicating that
the MHC haplotype has an impact on vector CTL epitope recognition
(13).
|
The mechanism of adenovirus recognition by CTL in humans remains controversial. Using different experimental conditions from ours, Smith et al. showed that de novo viral gene expression was not required to sensitize targets to lysis by adenovirus-specific CTL (23). In contrast, Flomenberg et al. reported that CTLs did not recognize input virion proteins (7). In the present study, we have provided compelling evidence that adenovirus-specific CTL recognition does not require de novo gene expression. In addition, we have demonstrated that capsid components introduced by an exogenous pathway resulted in MHC class I-associated peptide complexes that serve as targets for CTL recognition and have identified these components in two patients. Several experiments with other viral systems have demonstrated that exogenous proteins processed by target cells efficiently induce antiviral CTL responses (2, 19, 33). Moreover, Sigal et al. recently showed that dendritic cells presented antigens from virally infected nonhematopoietic cells, indicating that the exogenous MHC class I pathway is the major mechanism of CTL responses to nonhematopoietic virus-infected cells in vivo (22). Besides contributing to the elucidation of the immune mechanisms elicited by adenovirus in humans, our results have important implications for the design of gene therapy protocols since they demonstrate that the antiviral CTL response will not be reduced by using additionally deleted vectors.
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ACKNOWLEDGMENTS |
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This work was supported by grant 9252 from the Association pour la Recherche contre le Cancer (ARC) V.M.-F. was supported initially by a fellowship from ARC and subsequently by the Ligue Nationale contre le Cancer.
We thank Hedi Haddada for critical reading of the manuscript and Lorna Saint Ange for editing.
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FOOTNOTES |
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* Corresponding author. Mailing address: Département de Biologie Clinique, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. Phone: 33 1 42114478. Fax: 33 1 42115268. E-mail: farace{at}igr.fr.
Present address: Laboratoire d'Immunologie des Pathologies
Infectieuses et Tumorales, INSERM U445, Institut Cochin de
Génétique Moléculaire, Université R. Descartes,
Hôpital Cochin, 75014 Paris, France.
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Journal of Virology, August 2000, p. 7678-7682, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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