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Journal of Virology, May 2001, p. 4941-4946, Vol. 75, No. 10
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.10.4941-4946.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Patient-Specific Cytotoxic T-Lymphocyte
Cross-Recognition of Naturally Occurring Variants of a Human
Immunodeficiency Virus Type 1 (HIV-1) p24gag
Epitope by HIV-1-Infected Children
F.
Buseyne,1,*
M.-L.
Chaix,2
C.
Rouzioux,2
S.
Blanche,3 and
Y.
Rivière1
Laboratoire d'Immunopathologie Virale, URA
CNRS 1930, Institut Pasteur,1 and
Laboratoire de Virologie,2 and
Fédération de
Pédiatrie,3 Hôpital Necker-Enfants
Malades, 75015 Paris, France
Received 29 December 2000/Accepted 27 February 2001
 |
ABSTRACT |
We tested seven human immunodeficiency virus-infected children for
their cytotoxic T-lymphocyte (CTL) activities towards the p24gag QASQEVKNW epitope and its
nine variant sequences. Our data confirm that most, but not all, CTL
responses are broadly cross-specific. For the first time, we show the
high interpatient variability in cross-recognition of mutant CTL
epitopes. These interindividual variations in the CTL response to
the same epitope should be taken into account in the design and the
evaluation of vaccines.
| |
TEXT |
Human immunodeficiency virus (HIV)
infection is a major public health problem, in particular in developing
countries. Therefore, a vaccine against this virus is urgently needed
to reduce the propagation of the epidemic. The contribution of
cytotoxic T lymphocytes (CTL) in controlling HIV replication in
infected hosts has been well demonstrated, though they do not eradicate
the virus (15, 16). Meanwhile, vaccine studies in animal
models have shown that preexisting CTL can reduce viral load during
primary infection and eventually slow the progression of the disease
(15, 18). An important issue for vaccine development is
the antigenic diversity among different HIV isolates. In 1992, comparison of genetic sequences from various HIV strains led to the
definition of HIV type 1 (HIV-1) subtypes. Since then, the number of
known HIV-1 subtypes has been growing (21, 22). In order
to confer protection against most field isolates, immunogens able to
induce broadly cross-reactive CTL are required. In 1998, we showed that
HIV-specific CTL responses from children infected with various HIV
subtypes were mostly cross-reactive against two HIV clades
(5). At the same time, several other studies on vaccinated
or HIV-infected persons reached the same conclusion (1, 8, 11,
12, 19, 20, 28).
These previous studies described the cross-recognition of full-length
HIV proteins by bulk CTL from genetically diverse populations exposed
to different strains of HIV. They gave an appropriate evaluation of
cross-reactive CTL, at the level of the infected patient and at the
level of the population infected by various HIV subtypes. This approach
is worthy for estimation of the level of CTL cross-reactivity that may
be attained in vaccinated populations. However, it may overestimate the
cross-recognition at the level of single CTL epitopes for two main
reasons. First, the CTL response is multispecific, and distinct CTL
populations present in bulk cultures can recognize several CTL
epitopes on the same protein (6, 7). Second, some CTL
epitopes are conserved between several HIV subtypes. As the use of
target cells expressing full-length HIV proteins may have
overestimated the cross-recognition capacities of CTL, we studied the
capacity of CTL to recognize variant sequences of a single epitope.
When cross-recognition of a single epitope has been studied,
reactivity from only one CTL population was reported (8,
10, 20). Here, we tested several CTL lines specific for the same
epitope in order to establish if cross-recognition of variant
epitopes is shared by all CTL or is specific for each CTL
population. We chose the HIV p24gag
epitope, QASQEVKNW, because it is presented in
association with two HLA molecules, HLA-B53 (our results) and
HLA-B57 (14), and because several naturally
occurring variants have been reported (17). We found
that recognition of variant sequences of the CTL epitope was broad,
as the five responders recognized two to nine variant sequences. Most
importantly, we observed that the CTL responses from each
individual differed from the others by the identity of sequences
recognized and by the level of lysis of target cells expressing these sequences.
Recognition of HIV Gag protein and CTL epitope
QASQEVKNW by PBMCs after nonspecific
stimulation.
Seven children included in a longitudinal follow-up
study of their CTL activities were selected for their expression of
HLA-B53 or -B57, as determined by amplification refractory mutation
system PCR (4, 5). Peripheral blood mononuclear cell
(PBMC) samples exhibiting significant lysis against the HIV
p55gag protein were chosen for this study. The
patients were monitored at Hôpital Necker, Paris, France. The
legal guardians gave informed consent before the children entered the
study. Child EM100 was infected through transfusion of a contaminated
blood product. Mother-to-child transmission of HIV was responsible for
infection of the other children. Their infecting subtypes were
determined by heteroduplex mobility assay or sequencing of the Env
gene, as previously reported (5). Patients' clinical and
biological characteristics are summarized in Table
1.
Bulk CTL cultures were generated by mitogenic stimulation with
phytohemagglutinin (PHA) and expansion in the presence of recombinant
interleukin-2 (100 IU/ml; Chiron, Suresnes, France; a generous
gift
from R. Lebour) as described previously (
5). A standard
51Cr release assay was used to measure lysis of target
cells expressing
p55
gag from a clade A and a
clade B isolate, encoded by recombinant
vaccinia viruses vvTG6026 and
vvTG1144 (Transgène, Strasbourg,
France [
5]).
Cells from patients EM47 and EM74 recognized
p55
gag from both HIV isolates (Table
2). In contrast, cells from patient
EM23
recognized only p55
gag from the clade A isolate,
and CTLs from patient EM3 lysed only
target cells expressing
HIV clade B p55
gag.
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TABLE 2.
Recognition of CTL epitope
p24g,a,g QASQEVKNW by HIV-infected
children carrying HLA-B53 or HLA-B57 molecules
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Then, we tested the ability of the CTL lines to recognize the variants
of the QASQEVKNW epitope using synthetic peptides.
Peptides corresponding to the naturally occurring variants recorded
in
1997 (
17) for the p24(176-184) epitope were
synthesized by
Neosystem (Strasbourg, France) and obtained through the
Agence
Nationale de la Recherche sur le SIDA. Peptides corresponding
to
consensus sequences of major HIV clades A, B, C, D, and F are,
respectively, 25-17A (QATQEVKNW), 25-17B
(QASQEVKNW), 25-17C (QATQDVKNW),
25-17D (QASQDVKNW), and 25-17F (QATQEVKGW).
The five minor variants
are 25-17M1 (QATQAVKNW),
25-17M2 (QASQEVKNR), 25-17M3 (QASQEVKGW),
25-17M4 (EATQEVKGW), and 25-17M5 (QATQDVKDN).
After PHA stimulation,
one out of five CTL cell lines (EM47)
recognized peptides corresponding
to the QASQEVKNW CTL
epitope and its variant sequences. Target
cells pulsed with the
clade B index peptide as well as with pools
of peptides corresponding
to the four major clade variants and
the five minor variant sequences
were lysed by CTL cell line EM47
(Table
2).
Patient-specific patterns of CTL cross-recognition of
QASQEVKNW CTL epitope variants after
stimulation of PBMCs with peptides.
We first used PHA to
stimulate CTL because it will expand all CTL independently of their
specificity. PHA-stimulated PBMCs recognized full-length HIV
p55gag protein, but only one CTL population
recognized the p24gag QASQEVKNW
epitope (Table 2). Therefore, we performed antigen-specific stimulations of the CTL cell lines in order to increase the frequency of CTL specific for the epitope. We chose to use a mix of the 10 variant peptides corresponding to all sequences studied, to avoid
introducing biases in the amplification of CTL specific for a
particular sequence. Previously PHA-stimulated PBMCs were restimulated with autologous Epstein-Barr virus-transformed B cells (EBV-B cells) coated with a mix of the 10 peptides, each at
a final concentration of 1 µg/ml. Before mixing with responding cells
at a ratio of 1:1, EBV-B cells were irradiated at 100 Gy and washed
twice to eliminate unbound peptides. This procedure led to the
detection of lysis of peptide-pulsed target cells for four of the five
HLA-B53-positive patients and one of the two HLA-B57-positive patients
(Table 2). Figure 1 shows the recognition of each variant peptide by the responding CTL cell lines. Patient EM17
had the more focused response, as she recognized only peptides 25-17F
and 25-17M3 (Fig. 1A). Despite being infected with an HIV-1 clade D
isolate, she did not lyse targets pulsed with the consensus clade D
sequence of the epitope. A CTL cell line obtained 4 years later
from this patient had the same specificity for the 25-17F and 25-17M3
sequences (data not shown). Lysis of HIV-p55gag
clade B-expressing target cells (Table 2) was due to immunodominant effectors recognizing the HLA-B44-restricted HIV
p24gag SEGATPQDL epitope (data not shown).
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FIG. 1.
Recognition of the 10 variant sequences of CTL
epitope p24gag QASQEVKNW by CTL
cell lines from five responders. Autologous EBV-B cell lines were used
as target cells in a 51Cr release assay. Peptides were
tested at 1 µg/ml. The line indicates the level of significantly
positive lysis. (A) EM17, two peptide stimulations, effector/target
ratio (E:T) = 60:1. (B) EM23, one peptide stimulation, E:T = 20:1. (C) EM34, two peptide stimulations, E:T = 20:1. (D) EM47,
two peptide stimulations, E:T = 20:1. (E) EM47, PHA stimulation,
E:T = 60:1. (F) EM3, three peptide stimulations, E:T = 60:1.
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In contrast to patient EM17, the four other responders had broadly
cross-reactive responses to the epitope, as they recognized
four to
nine variant sequences. Patient EM23 is of African origin
and has been
infected with a clade B isolate. Her CTL efficiently
recognized four
sequences (25-17A, -B, -F, and -M3; Fig.
1B).
The 25-17D peptide was
also recognized, albeit with reduced efficiency.
Child EM34 is of
Caribbean origin. Unfortunately, typing of her
HIV type was not
performed, due to the lack of available samples.
She has been probably
infected by a clade B isolate. She had a
broad CTL response
directed against sequences 25-17A, -B, -F,
-M1, and -M3 (Fig.
1). The
fourth HLA-B53-positive patient, EM47,
had the widest spectrum of
cross-clade recognition. His PBMCs,
which were isolated in 1995 and
1998, efficiently recognized sequences
25-17A, -B, -C, -F, and -M5
(Fig.
1D and E). Low-level recognition
of variants 25-17D, -M1, -M2, or
-M3 was observed in one or both
samples tested. Of the two
HLA-B57-positive patients, only patient
EM3 recognized the CTL
epitope QASQEVKNW. He had a broad
cross-recognition
pattern, as four sequences (25-17A, -B, -F, and -M4)
were well
recognized (Fig.
1F).
The patient-specific response observed might be due either to the viral
strains infecting each subject or to host-specific
factors and in
particular to their T-cell receptor (TCR) repertoire.
Three of the four
children with broad CTL responses have been
infected with a clade B
isolate, and the fourth one (EM34) has
probably been infected by a
clade B strain, as she is of Caribbean
origin. As HIV typing is based
on the envelope sequence, one cannot
exclude the possibility that the
patients carry CTL sequences
different from the clade B consensus or a
recombinant HIV strain
(
23). Presence of variant sequences
of the CTL epitope in vivo
may lead to preferential expansion of
CTL specific for these variants.
However, vaccinees exposed to a single
HIV sequence have cross-reactive
CTL, suggesting that the viral strain
infecting the patient is
not the only factor influencing the CTL
specificity (
12). In
addition, two CTL clones
derived from the same patient (EM47)
differed widely in the variants
recognized (F. Buseyne and Y.
Rivière, unpublished results). From
various studies, it appears
that TCR repertoires selected in response
to defined peptide-major
histocompatibility complex (MHC) complexes can
vary from being
relatively limited to extremely diverse. What is more,
it has
been shown that the TCR repertoire specific for a peptide-MHC
complex of naïve, effector, or memory CTL differs significantly
between individual syngeneic mice (
2,
3). These
experiments
indicate that for the human population that displays high
genetic
diversity, the interindividual variability in the TCR
repertoire
will lead to different CTL responses to the same peptide-MHC
complex,
as was observed in this
study.
Recognition of endogenously synthesized QASQEVKNW CTL
epitope and HLA restriction.
Using a panel of
allogeneic target cells partially matched for some HLA molecules, we
checked that recognition of the epitope was HLA-B53-restricted
for patients EM17 and EM47 (Fig. 2A and B) and HLA-B57-restricted for patient EM3
(Fig. 2C). The four CTL cell lines recognizing peptides 25-17A and -B
(EM23, EM34, EM47, and EM3) also lysed target cells expressing
full-length p55gag clade A and B, indicating
that cross-clade recognition occurred when the epitope was derived
from intracellular synthesis and processing of the viral protein (Table
2). Peptide titration experiments showed that CTL had high affinity for
the epitope. Peptide concentrations giving 50% of maximal lysis
were 0.42 ng of peptide 25-17F/ml for patient EM17, 0.26 ng of peptide
25-17B/ml for patient EM34, and 0.32 ng of peptide 25-17A/ml for
patient EM47.
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FIG. 2.
CTL epitope p24gag
QASQEVKNW is presented by both HLA-B53 and HLA-B57.
Autologous and partially HLA-matched EBV-B cells were used as target
cells in a 51Cr release assay. (A) EM17, effector/target
ratio (E:T) = 10:1, peptide 25-17F at 10 ng/ml. (B) EM47, E:T = 20:1, peptide 25-17A at 1 µg/ml. (C) EM3, E:T = 10:1, peptide
25-17B at 1 µg/ml.
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The capacity of a peptide to bind multiple MHC molecules and,
consequently, to be immunogenic in the context of individuals
of
different MHC types has been referred to as degeneracy. The
p24
gag CTL epitope QASQEVKNW
described here is presented in the context
of HLA-B57
(
14). In the present study, we showed that HLA-B53
is able
to present the same peptide. In contrast to previous reports
where
degenerate epitopes were presented by members of the same
HLA
supertype (
13,
25,
27), the two HLA molecules presenting
the CTL epitope QASQEVKNW do not belong to the same HLA
supertype.
Indeed, HLA-B53 belongs to the B7 supertype, whereas
HLA-B57 has
been proposed to belong to the distinct HLA-B58 supertype
(
24).
However, degenerate presentation of CTL epitopes
from
Plasmodium falciparum by both HLA-B53 and HLA-B57 was
previously reported
(
9). Interestingly, both B7 and B58
supertypes accept hydrophobic
aliphatic or aromatic residues at the
C-terminal position of their
peptide ligands (
24). B58
supertype has a preference for small
aliphatic residues at position 2 (A, S, or T) that is reminiscent
of the requirement for amino acid
fixation in the small B pocket
of HLA-B53 (
26). In
conclusion, even if HLA-B53 and HLA-B57
belong to different supertypes,
their peptide-binding characteristics
are consistent with the
presentation of the same epitope, as we
observed
here.
With regard to peptide sequences, three were efficiently recognized by
most patients (variants A, B, and F), three were efficiently
recognized
by a single patient (variants C, M3, and M5), and four
were weakly
recognized (variants D, M1, M2, and M4). Differences
in recognition of
efficiently presented variants might be due
to a bias in the sequences
infecting the patients or in the TCR
repertoire, as discussed above.
The four poorly recognized peptides
may have reduced immunogenicity.
However, amino acid changes in
variant 25-17D are also present in other
variants that are well
recognized. In contrast, presence of the
positively charged R
in position 9 of variant 25-17M2 may decrease
binding to the F
pocket of HLA-B53, which prefers hydrophobic or
aromatic residues.
The two other weakly recognized variants have a
nonconservative
mutation in position 1 (25-17M4) or in position 5 (25-17M1). In
conclusion, it is likely that amino acid changes in these
three
naturally occurring mutants may lead to decreased
immunogenicity.
Conclusions.
In the present work, we have looked at the
recognition of 10 naturally occurring variants of the HIV
p24gag QASQEVKNW CTL epitope. The
specificity of our approach was to investigate the cross-recognition of
variants of a defined CTL epitope by several patients, whereas
former studies tested a single CTL population specific for each
epitope (8, 10, 20). Thus, our approach shows that the
pattern of cross-recognition is dependent on the patients tested, as
some patients had a focused response whereas others were broadly
cross-reactive (Fig. 1). Most importantly, each patient recognized a
distinct set of variants. This interpatient variability in CTL
cross-recognition of variant sequences is described for the first time
in HIV-infected patients and should be taken into account as a factor
that may influence the response to and the efficacy of an HIV vaccine.
Because of the broad cross-clade reactivity of CTL observed in former
studies (
1,
5,
8,
11,
12,
19,
20,
28),
it is believed that
vaccines based on a single immunogen will
be sufficient to protect
against most field isolates. This is
true for the most conserved
epitopes and if several epitopes are
present in the vaccine.
The present results corroborate the broad
cross-clade reactivity of CTL
at the level of a single epitope
for the majority of patients
studied, though some patients had
a more focused CTL response. The
actual trend in vaccine strategies
is to incorporate additional HIV
genes, which have been shown
to encode a significant number of
determinants recognized by CTL.
It is hoped that each of these
additional sequences will result
both in an added breadth in the CTL
response as well as a greater
response rate among vaccinees. The
patient-specific pattern of
CTL cross-recognition observed in the
present study strongly supports
the use of vaccine strategies designed
to induce a polyclonal
CTL response, as the response to a defined CTL
epitope might differ
significantly among
individuals.
| |
ACKNOWLEDGMENTS |
This work was supported by Institut Pasteur, Agence Nationale de
Recherche sur le SIDA, and SIDACTION. Y.R. is an Elisabeth Glaser Scientist.
We thank F. Porrot and B. Corre for the follow-up of CTL activities
from children presented in this study and E. Bui for collecting clinical data. Genotyping was performed by F. Gotch at Chelsea and
Westminster Hospital, London, United Kingdom.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Laboratoire
d'Immunopathologie Virale, Département SIDA et
Rétrovirus, Institut Pasteur, 28 rue du Dr. Roux, 75015 Paris,
France. Phone: 33 1 45 68 88 99. Fax: 33 1 40 61 32 98. E-mail:
florence{at}pasteur.fr.
| |
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Journal of Virology, May 2001, p. 4941-4946, Vol. 75, No. 10
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.10.4941-4946.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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