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Previous Article | Next Article 
Journal of Virology, April 2001, p. 3984-3987, Vol. 75, No. 8
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.8.3984-3987.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Degenerate Immunogenicity of an HLA-A2-Restricted Hepatitis B
Virus Nucleocapsid Cytotoxic T-Lymphocyte Epitope That Is Also
Presented by HLA-B51
Robert
Thimme,1
Kyong-Mi
Chang,1,2
Janell
Pemberton,1
Alessandro
Sette,3 and
Francis V.
Chisari1,*
Department of Molecular and Experimental
Medicine, The Scripps Research Institute, La Jolla, California
920371; Department of Medicine,
University of Pennsylvania and Philadelphia Veterans Administration
Medical Center, Philadelphia, Pennsylvania
191042; and Epimmune, Inc., La Jolla,
California 921213
Received 30 November 2000/Accepted 16 January 2001
 |
ABSTRACT |
The recent identification of hepatitis B virus (HBV) epitopes
restricted by multiple HLA alleles has greatly expanded the epitope
repertoire available for T-cell-mediated therapeutic vaccine development. The HLA-B51-restricted peptide HBc19-27 is
particularly interesting because it is located entirely within the
HLA-A2-restricted HBc18-27 epitope. Here we show that
HLA-B51-restricted cytotoxic T lymphocytes specific for HBc19-27
from a patient with acute HBV infection were also able to lyse
HLA-B51-positive target cells pulsed with HBc18-27 and to produce
gamma interferon when stimulated by that peptide, implying that
HBc18-27 can be presented by HLA-B51 as well as by HLA-A2. These
results demonstrate the concept of degenerate immunogenicity across HLA
class supertype boundaries in a human viral disease setting. In
addition, they could facilitate the development of an epitope-based
therapeutic vaccine to terminate chronic HBV infection that could
provide a broad and diverse population coverage with a single peptide.
| |
TEXT |
It has been shown previously that
the peripheral blood cytotoxic T-lymphocyte (CTL) response to hepatitis
B virus (HBV) is polyclonal and multispecific in patients with acute
viral hepatitis (2, 7-9, 12). The CTL response persists
indefinitely after recovery, and it is maintained by continued
antigenic stimulation by residual virus that persists, apparently
harmlessly, in healthy convalescent individuals (11). In
contrast, the CTL response to HBV is relatively weak in patients with
chronic HBV infection, except during spontaneous disease flares or
interferon (IFN)-induced recovery, when it is readily detectable
(13). These observations have generated interest in
therapeutic approaches to stimulate the CTL response to HBV in
chronically infected patients.
The recent discovery that multiple class I alleles can recognize common
sequence motifs (supermotifs) led to the identification of groups of
alleles (supertypes) that recognize similiar motifs (15-18). For example, the B7 supertype (e.g., B*0702,
B*3501, B*5301, B*5401, and B*5101) recognizes 8- to 11-mer peptides
with P at position 2 and either A, I, L, M, V, F, W, or Y at the
carboxy terminus, while the HLA-A2 supertype (e.g., A*0201, A*0204,
A*0205, A*0206, A*0207, and A*6802) binds peptides containing L, V, M, I, T, A, or Q at position 2 and L, I, V, M, A, or T at the carboxy terminus.
Highly conserved HBV peptides that bind with high affinity to several
members of a given supertype have the potential of being degenerate
immunogens. Degenerate immunogenicity is defined as the capacity of a
single peptide to be immunogenic in the context of multiple HLA
molecules (15). Recognition of the same peptide by
completely unrelated class I molecules can also theoretically occur if
different HLA-binding motifs are nested within the peptide. An
interesting example of this recognition is provided by the HBV core
(HBc) region from positions 18 to 27 (1), which contains two nested epitopes, each capable of binding to a different class I
supertype. In this case the nested recognition involves the HLA-A2
supertype-restricted HBc18-27 epitope (FLPSDFFPSV) and the
HBc19-27 epitope (LPSDFFPSV), which binds multiple HLA-B7 supertype alleles, especially HLA-B51, with high affinity
(18).
The precise nature of the HBc18-27-derived peptide that is bound by
HLA-B51 is unresolved. To address this question, we analyzed the class
I-restricted CTL response to HBc18-27 and HBc19-27 in an
acutely infected HLA-A2-negative, HLA-B51-positive patient during and
after resolution of disease, and we asked if the HLA-B51-restricted HBc19-27-specific CTL from the patient were able to recognize the
HLA-A2-restricted peptide HBc18-27 in the context of HLA-A2 and
HLA-B51.
CTL response to an HLA-B51-restricted HBc epitope
during acute HBV infection.
Peripheral blood mononuclear
cells (PBMC) of an HLA-A2-negative, HLA-B51-positive patient with acute
HBV infection who ultimately resolved the infection were stimulated for
2 weeks with peptide HBc19-27, which binds with high affinity (50%
inhibitory concentration [IC50] of 9 nM) to multiple
HLA-B7 supertype alleles, including HLA-B51 (4, 18). For
these experiments, the synthetic peptide was added at 10 µg/ml, and
recombinant HBcAg was added at 1 µg/ml as a source of T-cell
help during the first week of stimulation. On days 3 and 10, 1 ml of
RPMI 1640 with 10% (vol/vol) human AB serum and recombinant
interleukin-2 (Hoffmann-La Roche, Inc., Nutley, N.J.) at 20 U/ml (final
concentration) was added to each well. On day 7, the cultures were
restimulated with peptide (10 µg/ml), recombinant interleukin-2 (20 U/ml), and 106 irradiated (3,000 rad) autologous feeder
cells. On day 14, the cells were tested for the ability to lyse
autologous or allogeneic HLA-matched or HLA-mismatched
51Cr-labeled Epstein-Barr virus (EBV)-transformed
B-lymphoblastoid cell lines that had been incubated overnight with
synthetic peptides at 10 µg/ml in a 4-h 51Cr release
assay exactly as previously described (4). Specific cytolytic activity was easily detected using peptide-pulsed autologous target cells as well as peptide-loaded allogeneic target cells that
were matched with the effector cells only at the HLA-B51 locus (Fig.
1). Next, the HLA-B51-restricted,
HBc19-27-specific CTL lines were tested for the ability to
recognize endogenously synthesized nucleocapsid antigen by using
allogeneic HLA-B51-positive target cells that had been infected with
vaccinia virus that directs the synthesis of the HBV core protein by
the cell (14). A significant level of specific cytolytic
activity was detected (Fig. 1), demonstrating that HBc19-27 is
generated by the intracellular processing of endogenously synthesized
HBV core and that these CTL are likely primed in vivo during HBV
infection. We also tested the ability of HBc19-27-specific CTL
lines to produce IFN-
following activation using reagents obtained
from PharMingen (San Diego, Calif.) and a staining procedure previously
well described (10). As shown in Fig.
2B, nearly 20% of the CD8+ T
cells in the peptide-stimulated cultures produced IFN- when stimulated with the highest concentration of HBc19-27, and the fraction of IFN- producing CD8+ T cells decreased in a
peptide dose-dependent manner.
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FIG. 1.
Recognition of endogenously synthesized HBcAg by
HBc19-27-specific CTL lines and HLA restriction analysis.
PBMC from the patient were stimulated for 2 weeks with HBc19-27 and
then tested for CTL activity against either autologous, partially HLA
matched or mismatched peptide HBc19-27-loaded EBV-transformed
B-lymphoblastoid target cells or allogeneic HLA-B51-positive target
cells that were infected at a multiplicity of infection of 10 with
wild-type (wt) or recombinant vaccinia viruses that express HBc as
previously described (6). The effects/target ratio used
was 50:1. When allogeneic cells were used, HLA-B51 was the only shared
allele and the target cells were not positive for other members of the
B7 and A2 superfamily.
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FIG. 2.
Presentation of peptides HBc18-27 and
HBc19-27 to HBc19-27-specific CTL. PBMC were stimulated
for 2 weeks with HBc19-27, and then their cytolytic activity was
measured against HLA-B51-positive, HLA-A2-negative target cells pulsed
with various concentrations of HBc19-27 and HBc18-27 (A).
Similarly stimulated PBMC were analyzed for simultaneous cell surface
CD8 expression and intracellular IFN- production after 5 h of
stimulation with various concentrations of both peptides (B), and
the number of IFN--producing cells was compared to the number of
cells observed in the absence of peptides.
|
|
HLA-B51-restricted, HBc19-27-specific CTL also recognize
HBc18-27.
Since the HLA-B51-restricted HBc19-27
epitope is contained entirely within an HLA-A2-restricted
HBc18-27 epitope that binds to HLA-A2 with very high affinity
(IC50, 2.5 nM) (16), we asked if both of these
peptides could be recognized by HLA-B51-restricted HBc19-27-specific T cells. We did not expect the CTL to recognize HBc18-27 since this peptide does not bind to HLA-B51
(IC50, >25,000 nM) in liquid-phase binding assays just as
HBc19-27 does not bind to HLA-A2 (IC50, >25,000
nM) (4, 16, 18). Interestingly, however, the
HLA-B51-restricted HBc19-27-specific CTL lysed HBc18-27- and HBc19-27-pulsed HLA-B51-positive target cells (Fig. 2A)
and produced IFN- (Fig. 2B) equally efficiently at all peptide
concentrations. Furthermore, the lytic activity and IFN- production
profiles were nearly identical at the different peptide concentrations tested. These results contrast with the failure of HBc18-27 to bind
to HLA-B51 in a liquid-phase peptide binding assay, raising the
possibility that HBc18-27 may have been contaminated with the
shorter peptide HBc19-27 or that it may have been converted to that
peptide in vitro. Contamination of HBc18-27 with HBc19-27 and
vice versa was excluded by reverse-phase high-pressure liquid chromatography (HPLC) and electrospray spectrometry of the original peptide stocks. As shown in Fig. 3,
peptide HBc19-27 displayed one major peak and three minor peaks by
HPLC and a molecular weight of 1,007.0 by mass spectroscopy. In
contrast, HBc18-27 displayed one major peak and two minor peaks,
all of which had different elution times than the peaks observed for
HBc19-27, and it displayed a molecular weight of 1,154.2 by mass
spectroscopy. Furthermore, electrospray spectrometry showed that there
was no overlap in the mass of the HPLC peaks from HBc19-27 (from
860.4 to 1,007.8) and HBc18-27 (from 1,154.2 to 1,210.8) (data not
shown).
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FIG. 3.
HPLC chromatogram and mass spectrogram of HBc18-27
and HBc19-27. Peptide HBc19-27 displayed one major peak and
three minor peaks by reverse-phase HPLC and a molecular weight of
1,007.0, determined by mass spectroscopy. In contrast, HBc18-27
displayed one major peak and two minor peaks and a molecular weight of
1,154.2. The minor HPLC peaks in the two peptide preparations were also
analyzed by mass electrospray spectrometry and shown to represent
unrelated minor species (data not shown).
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We then tested the possibility that HBc18-27 might be trimmed to
HBc19-27 by serum or cellular proteases in the CTL and IFN- production assays. In these experiments, we compared the abilities of
HLA-B51-positive antigen-presenting cells (APC) to present the two
peptides to HLA-B51-restricted HBc19-27-specific CD8+ T
cells in the presence or absence of fetal calf serum, in the presence
or absence of protease inhibitors, and using paraformaldehyde-fixed or
unfixed autologous or allogeneic HLA-B51-positive target cells as APC.
Specifically, allogeneic HLA B51-positive target cells were loaded with
10 µg of HBc18-27 or HBc19-27 per ml or no peptide overnight
and then added to the HLA-B51-restricted HBc19-27-specific CTLs
after they were washed extensively (six times). Five hours later,
IFN- production of the CTL was measured exactly as previously described (10). In some experiments, APC were fixed with
1% paraformaldehyde for 30 min and then cultured overnight with the peptides in the presence or absence of a cocktail containing 10 different protease inhibitors (Complete; Boehringer Mannheim, Mannheim,
Germany) with a wide spectrum of protease inhibitory activity. Table
1 shows that HBc18-27 was presented
as efficiently as HBc19-27 to HLA-B51-restricted HBc19-27 CTL
in the absence of serum, in the presence of protease inhibitors, and
when the APC were fixed or not fixed. Furthermore, both peptides were
identical in the ability to trigger peptide-specific IFN- production
whether they were added to fixed APC for 15 min or 24 h before
exposure to the CTL (Fig. 4) and also
when they were added to fixed or unfixed APC over a range of
concentrations spanning 5 orders of magnitude (Fig.
5). While it is still possible that these
precautions did not completely prevent conversion of HBc18-27 to
HBc19-27, the virtual identity of the peptide-specific IFN-
responses to HBc18-27 and HBc19-27 under these conditions
(Table 1; Fig. 4 and 5) suggests that artifactual processing of the
longer peptide was not responsible for its ability to stimulate the
HLA-B51-restricted HBc19-27-specific CTL.
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TABLE 1.
Ability of HLA-B51-positive APC to present HBc18-27
(10 µM) and HBc19-27 (10 µM) to HLA-B51-restricted HBc19-27
CTL in the presence or absence of fetal calf serum, in the presence
or absence of protease inhibitors, and using paraformaldehyde-fixed or
unfixed autologous or allogeneic HLA-B51-positive target cells as
APC
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FIG. 4.
Presentation after different APC loading times with
peptides. Fixed HLA-B51 positive autologous APC (EBV-transformed
B-lymphoblastoid cells) were loaded with HBc18-27 or HBc19-27
and cultured in serum-free medium in the presence of protease
inhibitors as described in Materials and Methods. After different time
periods of peptide loading, the APC were extensively washed and then
added to HBc19-27-specific, HLA-B51-restricted CTL;
peptide-specific (pep. spec.) IFN- production was measured after a
5-h stimulation.
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FIG. 5.
Peptide presentation of fixed and unfixed APC. Fixed or
unfixed HLA-B51-positive APC were loaded with different concentrations
of HBc18-27 or HBc19-27 for one h in serum-free medium,
extensively washed, and then added to the HBc19-27-specific,
HLA-B51-restricted CTL. Peptide-specific (pep. spec.) IFN-
production was measured after a 5-h stimulation and compared to IFN-
production in the absence of peptides.
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The foregoing results suggest that the HBc18-27 peptide binds very
efficiently to HLA-B51 at the cell surface despite its failure to do so
in the liquid-phase binding assay used in this study. This result is
not entirely unexpected since HBV polymerase 354-363-specific
HLA-B51-restricted CTL are able to recognize the epitope despite
its failure to bind the allele in a liquid-phase binding assay
(18). This apparent contradiction might be explained if
the conformation of HLA-B51 at the cell surface or the presence of
other cell surface molecules allows it to bind the longer peptide. Alternatively, it is conceivable that the T-cell receptor might stabilize the T-cell receptor-peptide-major histocompatibility MHC
complex in this case as has been suggested for a DRB*1302-restricted tetanus toxoid peptide, where analogues with very unstable binding were
still able to stimulate T cells equally well (5). Whatever the explanation, these results suggest that degenerate immunogenicity (e.g., the capacity of a given peptide to be immunogenic in the context of multiple HLA molecules) can occur across HLA supertype boundaries, in this case the HLA-B7 and HLA-A2 supertypes. Since it has
been recently suggested that the HBc18-27 epitope can
stimulate HLA class II restricted T-cell responses (3),
the breadth of its reactivity across the boundaries of class I and II
alleles and HLA supertypes strongly suggests that HBc18-27 should
be included in the future design of multiple-epitope-based
therapeutic vaccines.
| |
ACKNOWLEDGMENTS |
We thank Sue Dastrup and Priscilla Crisler for coordinating the
patients' samples, Scott Southwood and John Sidney (Epimmune) for the
binding assays, Kelly Wassmund (Research Genetics) and Chi Yang (SynPep
Corporation) for the electrospray spectrometry, Stefan Wieland for many
helpful discussions, Andrea Achenbach for assistance with the
manuscript, and the patient who made this study possible.
This study was supported by grants AI 20001 and RR 00833 from the NIH
and contract N01 AI 95362. R. Thimme was supported by grant TH 719/1-1
from the Deutsche Forschungsgemeinschaft, Bonn, Germany, and a
postdoctoral training fellowship from the American Cancer Research
Institute, New York, N.Y. K.-M. Chang was supported by NIH training
grant 2T32DKO7202 through the University of California, San Diego, the
American Liver Foundation's Amgen Postdoctoral Research Fellowship
Award, and an Amgen/AASLD/ALF Research Development Award.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Molecular and Experimental Medicine, SBR-10, The Scripps Research
Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858)
784-8228. Fax: (858) 784-2960. E-mail address:
fchisari{at}scripps.edu.
Manuscript no. 13467-MEM from the Scripps Research Institute.
| |
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Journal of Virology, April 2001, p. 3984-3987, Vol. 75, No. 8
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.8.3984-3987.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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