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Journal of Virology, May 1999, p. 4447-4451, Vol. 73, No. 5
Institut Cochin de Génétique
Moléculaire (ICGM),
Received 26 June 1998/Accepted 21 January 1999
We have optimized the induction of antiviral cytotoxic T
lymphocytes (CTL) in rhesus macaques by a lipopeptide
vaccine containing seven peptides from simian immunodeficiency virus
(SIV) Nef and Gag proteins and a strong T-helper peptide from tetanus
toxoid (TT) that is promiscuous in humans (peptide TT 830-846). Two of the eight immunized macaques showed T-helper (Th) cell proliferation and a specific synthesis of gamma interferon in response to TT 830-846 peptide. They also showed multispecific cytotoxic activity against
three to five of the immunizing SIV peptides. These results show the
importance of a strong specific type 1 Th response for inducing a
multispecific CTL response in vivo, which is essential for the
development of an anti-human immunodeficiency virus vaccine.
Virus-specific
CD8+ responses are essential for immune protection
against several viruses (8, 34, 37). Hence, successful vaccines must induce cellular immunity mediated by CD8+.
Cytotoxic T lymphocytes (CTLs) are involved in the control of the viral
load during human immunodeficiency virus (HIV) infection (4, 7,
17, 18) and seem to be very important in vaccine-induced protection (12). However, as they exert considerable
selective pressure in both primary and late-stage HIV infections, they
may select for escape mutant viruses (5, 14, 28). We have
demonstrated that the induction by lipopeptides of CD8+
CTLs recognizing only one epitope in the simian immunodeficiency virus
(SIV)-infected macaque model is not sufficient to protect against SIV
and may favor the selection of variant viruses and the emergence of
escape mutant viruses (23). Thus, the induction of
multispecific CTLs that recognize several virus isolates by giving an
appropriate vaccine is likely to be essential to prevent selection of
mutant or variant viruses.
We have now immunized eight rhesus macaques (Macaca mulatta)
(92102, 92105, 92109, 92117, 92120, 92125, 92127, and 92129) with
tetanus toxoid (TT) (500 µg per monkey) in incomplete Freund adjuvant
(IFA) (three subcutaneous and intramuscular injections given at 1-month
intervals). Indeed, initial vaccination with a carrier protein induces
helper T (Th) memory cells that may then be exploited by using selected
relevant T epitopes from the same protein to boost B cell and CTL
responses (15, 31). The proliferation of peripheral blood
mononuclear cells (PBMCs) against TT was measured by monitoring
3H-labeled thymidine incorporation 1 month after the last
immunization; it was significant for all macaques (data not shown).
Five months later, there was a significant Th-specific response to
lipopeptide TT 830-846 in only two macaques, 92109 and 92129 (data not shown).
Seven months after the last TT immunization, the macaques were given
three subcutaneous injections of a mixed-micelle formulation of eight
lipopeptides in sterile water (500 µg of each lipopeptide) without
any adjuvant at 1-month intervals. This immunization procedure was thus
compatible with human vaccination. Five sequences of lipopeptides were
selected from the SIV Nef (LP1, amino acids [aa] 101 to 126; LP2, aa
125 to 147; LP3, aa 155 to 178; LP4, aa 201 to 225; and LP5, aa 221 to
247), and two were selected from the Gag protein (LP6, aa 165 to 195, and LP7, aa 246 to 281). These were identical to
sequences previously reported (6, 7, 10, 23) except for
the introduction of an additional
N Lipopeptide TT 830-846 Th-specific responses were assessed 6 months
after the last lipopeptide immunization; they showed that the same two
macaques (92109 and 92129) always had strong responses to lipopeptide
TT 830-846 (data not shown). We therefore investigated whether
these results depended upon a particular type 1 or type 2 profile and analyzed the CD4+ or CD8+ nature of
these T cells. We first assessed lymphokine production by PBMCs which
had undergone a short stimulation in vitro with LP-TT by using a
sensitive enzyme-linked immunospot (ELISPOT) assay for gamma
interferon (IFN- The lipopeptide-induced CTL responses were examined after the last
mixed-micelle immunization by stimulating macaque PBMCs with a
mixture of the seven long free peptides without the helper TT 830-846 epitope and testing them against autologous B lymphoblastoid cell lines
(B-LCLs) sensitized by the same long peptides. On the day of the
chromium release test (CRT), effector cells were >70% CD8+ T cells for every test performed, as might be expected
for class I-restricted antigen-specific CTLs. Most (seven) of the eight immunized macaques had CTL activity (Fig.
2), and macaques 92109 and 92129 had
strong and multispecific CTL responses to five and three long peptides,
respectively. We tested overlapping short peptides (8 to 11 aa)
spanning the sequence of the long peptides (Table
1) to identify six epitopes recognized by
CTLs from macaque 92109, three of which (NEF 169-178, NEF 215-225, and
GAG 266-275) were very strongly recognized. Three others caused less
lysis. Similarly, the CTLs from macaque 92129 recognized four peptides (NEF 128-136, NEF 201-211, NEF 211-219, and NEF 169-178). Macaque 92127 had CTLs that recognized two long peptides with a cytotoxic activity
lower than those of peptides from macaques 92109 and 92129 (Fig. 2).
Macaques 92125, 92120, 92102 and 92105 had CTLs that recognized a
single peptide, while the CTLs from macaque 92117 recognized no
peptide. A maximum of one short peptide in every long peptide
recognized was identified for macaques 92125, 92127, and 92105 (Table
1). In contrast, in macaques 92102 and 92120, no short epitopic
peptides within long peptides were identified. CTL activities persisted
in all the macaques for 9 to 10 months after the last lipopeptide
immunization and did not result from in vitro induction of primary CTL
responses, since they were not detected after antigen-specific
stimulation of naive PBMCs from the seven CTL responders (data not
shown). The multispecific activity in the two responder macaques was
then associated with significant type 1 Th (Th1) responses to the TT
830-846 peptide after immunization with either TT or lipopeptide
(P < 0.05 by the chi-square test). A recent in vivo
study has shown that T helper subset cells with Th1 profiles regulate
both the sensitivity and the frequency of epitope-specific CTL
responses in mice (29). A relationship between significant
Th responses and strong, persistent CTLs with high frequencies of CTL
precursors (CTLp) in vivo in mice (3, 16, 19, 24, 32, 35)
and humans vaccinated with lipopeptides against chronic hepatitis B
virus infection (20, 39) has also been described.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Type 1 CD4+ T-Cell Help Is Required for Induction of
Antipeptide Multispecific Cytotoxic T Lymphocytes by a Lipopeptidic
Vaccine in Rhesus Macaques
Université René
Descartes,Université de Lille II,
ABSTRACT
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-palmitoyl-lysylamide residue at the C
terminus (23). In addition, to improve CTL induction, a
lipopeptide containing promiscuous human Th epitope from TT-derived
peptide, aa 830 to 846, Ac-QYIKANSKFIGITELKK, referred to
herein as LP-TT; this was preferred to peptide 830-843 because of
its greater solubility and was synthesized with a modification of the
N-terminal extremity by an acetyl group, to avoid any heterogeneity that might be produced by formation of the pyroglutamyl analog upon
storage. The mixed-micelle formulation was obtained by dissociating each component in concentrated acetic acid (80%) before mixing and
sterilization by filtration. Dilution resulted in the formation of
mixed micelles or aggregates that, statistically, contained each of the constituents.
) adapted from Scheibenbogen et al. (33).
Only the PBMCs from the two macaques showing proliferative assay
response (92109 and 92129) specifically synthesized IFN- (Fig.
1a). We then confirmed the
CD4+ nature of the effector T cells that secreted IFN-
in response to lipopeptide TT 830-846 by using the ELISPOT
assay to measure IFN- levels in PBMCs, CD4+-depleted
PBMCs, and CD8+-depleted PBMCs (Fig. 1b). The
LP-TT-specific response of the CD8+-enriched population was
completely abrogated. Conversely, depletion of CD8+ cells
did not decrease the number of IFN- spot-forming cells (SFCs),
indicating that the IFN- secretion induced by LP-TT was mediated by
CD4+ T cells.
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FIG. 1.
Synthesis of IFN- by CD4+ lymphocytes
after LP-TT stimulation in macaques 92109 and 92129. (a) Helper
peptide-specific IFN- SFCs in PBMCs from the eight macaques were
analyzed after the third mixed-micelle lipopeptide immunization. The
ELISPOT assay was performed 7 days after one short in vitro
stimulation. Briefly, PBMCs (2.5 × 106/ml) were
cultured for 3 days in 24-well microtiter plates (Costar, Cambridge,
Mass.) in complete medium, with 5 µM LP-TT or with 5 µM irrelevant
LP (Nef HIV 66-97) (LP-i). IL-2 (Boehringer, Mannheim, Germany) was
then added to each well (10 IU/ml), and incubation was continued for 4 days. Effector cells were then washed, counted, and seeded in duplicate
in 96-well nitrocellulose plates (Multi-Screen HA; Millipore, Bedford,
Mass.) that had been coated with the mouse anti-human IFN- capture
monoclonal antibody (Genzyme, Russelheim, Germany) (8 µg/ml in
carbonate buffer) and blocked with complete medium. Effector cells were
incubated at 105 and 2 × 105 per well
with 5 µM LP-i (white columns) or 5 µM LP-TT (black columns) for
48 h in complete medium containing 20 IU of IL-2/ml. The ELISPOT
assay was performed as previously described (33). Responses
were considered significant if there were a minimum of five SFCs per
well and if this number was at least twice that obtained with the
negative control. (b) A depletion assay was done using anti-CD4 or
anti-CD8 monoclonal antibodies (MAbs) on the Th cell responder macaques
(90109 and 92129) to obtain CD4+-depleted PBMCs and
CD8+-depleted PBMCs, together with whole PBMCs.
PBMCs were incubated for 30 min with cocktails of anti-human CD8
(DAKO, Glostrup, Denmark; Becton Dickinson, Mountain View, Calif.; and
Ortho Diagnostic Systems, Raritan, N.J.) (1 µl of
each/106 cells) or cocktails of human anti-CD4 (DAKO; Sigma
Chemical Co., St. Louis, Mo.; and Ortho Diagnostic Systems) (1 µl of
each/106 cells) MAbs coated on Dynabeads in 500 µl of
complete medium on ice (BioMag goat anti-mouse immunoglobulin G;
PerSeptive Biosystems, Framingham, Mass.). Conjugate-coated cells were
then removed with a magnet (Dynal) and cultured in vitro for 5 days.
Finally, they were tested in the ELISPOT assay.
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FIG. 2.
Cytotoxic activities of the seven responder macaques.
Anti-peptide CTL lines were obtained by pulsing for 2 h macaque
PBMCs (10 × 106 cells/ml) with a mixture of the
five Nef and two Gag free long peptides (10 µM each) corresponding to
the immunizing lipopeptides. The cells were then washed and resuspended
(106/ml) in complete medium and incubated in 24-well
microtiter plates. After 3 days of incubation, IL-2 was added to each
well (10 IU/ml). On days 7 and 14, effector cells were washed and
diluted to 106/ml, placed in new plates, and stimulated
with irradiated peptide-pulsed (10 µM each) autologous PBMCs
(10 × 106/ml) for 2 h and then diluted to
106/ml in complete medium containing 20 IU of IL-2/ml
(effector/stimulator ratio, 1:1). A CRT was performed after the third
stimulation of CTL lines. The target cells were autologous B-LCLs
(immortalized by the herpesvirus papio) alone or incubated overnight
with various long peptides (10 µM/ml). The CRT was considered
positive if the specific 51Cr release observed in the
presence of peptide-pulsed target cells exceeded by 10% that observed
for B-LCLs without peptide at two effector/target (E/T) ratios. Only
the positive cytotoxic responses against peptide-sensitized target
cells of the seven responder macaques are shown.
TABLE 1.
Epitopic specificities found in five immunized macaques
Synthetic peptides modified at one end by addition of a lipid moiety are highly immunogenic for T and B cell responses in vivo (2, 11, 22). Lipopeptides also facilitate the presentation of peptides by major histocompatibility complex (MHC) class I molecules (11), which may be due to their ability to rapidly cross the cell membrane and enter the cytoplasm of intact cells (21, 38). Last, large synthetic lipopeptides can be processed in a manner similar to whole exogenous proteins and become associated with MHC class II molecules. We chose to use the promiscuous helper peptide TT 830-843 that binds to several HLA-DR molecules (20, 26, 27, 39) in this study. Other promiscuous peptides could be used in humans, including PADRE epitopes, which bind to 14 different HLA-DR molecules (9). This degenerate binding specificity of peptides could overcome the problem of the extreme polymorphism of HLA-DR molecules in humans. We used the promiscuous TT peptide because it provides adequate T cell help to induce CTLs, as shown in a human vaccine trial against chronic hepatitis B virus (20, 39). We believe that an immunizing formulation with mixed micelles that statistically contain each of the constituents allows the physical association of Th and CTL peptides and may favor the presentation of peptides to T helper lymphocytes and CTLs by the same antigen-presenting cell, which is essential for optimal productive interactions and collaboration between Th cells and CTLs (36).
The breadth of the CTL peptide recognition spectrum in only two macaques (92109 and 92129) in this study could have been due to the heterogeneity of their MHC class I molecules. This is unlikely in the light of the results of much larger studies including our previous experiments (7, 23). We obtained 16 CTL responders from 22 macaques immunized with lipopeptides and found that 14 of them had mono- or bispecific CTL responses. In addition, these two macaques belong to the same cohort as the six Th nonresponders, and all these macaques may share the same MHC class I molecules. Therefore, induction of multispecific CTLs is unlikely to be due to particular MHC class I molecules. The mono- and bispecific responder macaques may not have had MHC class II molecules suitable for presenting immunizing TT 830-846 lipopeptide. This problem could be overcome in humans by using several promiscuous peptides that are presented by a majority of MHC class II molecules. Adding another T helper epitope or synthesizing more immunogenic lipopeptides containing modified peptides (25) may better stimulate a Th1 response for inducing anti-HIV multispecific CTL responses. HIV-specific Th epitopes would be more relevant to induce strong helper activity at the time of HIV infection. Few HIV Th epitopes have been described to date, but the restoration of anti-HIV proliferative responses (1, 13, 30) by highly active antiretroviral treatment of primary infected humans may provide a better definition of Th epitopic regions.
Finally, our findings suggest that anti-TT 830-846 T lymphocytes with a
Th1 profile are most important and indicate that soluble factors like
IFN-, and probably interleukin 2 (IL-2), help to induce optimal
differentiation of CTL responses, leading to multispecific cytotoxic
responses. These results appear to be promising for the future
development of peptide vaccines to protect against HIV infection.
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ACKNOWLEDGMENTS |
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This work was supported by the Agence Nationale de Recherche sur le SIDA, the Institut Pasteur de Lille and by the Centre National de Recherches Scientifiques. Lorenzo Mortara holds a Sidaction/Ensemble Contre le SIDA fellowship.
We thank Claire Bony and Pascale Villefroy for excellent technical assistance and Isabelle Bouchaert for technical advice on phenotypic analysis. The English text was edited by Owen Parkes.
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FOOTNOTES |
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* Corresponding author. Mailing address: ICGM, INSERM U445, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. Phone: (33) 01 44 07 18 21. Fax: (33) 01 44 07 14 25. E-mail: mortara{at}cochin.inserm.fr.
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Journal of Virology, May 1999, p. 4447-4451, Vol. 73, No. 5
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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