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Journal of Virology, February 1999, p. 1715-1718, Vol. 73, No. 2
Institut für Impfstoffe,
Bundesforschungsanstalt für Viruskrankheiten der Tiere,
Tübingen, Germany
Received 19 August 1998/Accepted 4 November 1998
Experimental infection of rats with Borna disease virus (BDV) and
natural BDV infection of horses and sheep leads to a virus-induced T-cell-mediated immunopathology in the central nervous system. Earlier
work revealed the importance of the BDV-specific T-cell response and of
CD8+ effector cells in particular in the
destruction of virus-infected cells. Evidence was also presented
that this major histocompatibility complex class I-restricted lysis
detected in vitro might play a functional role in the
immunopathogenesis of Borna disease. The present study employed
different vaccinia virus recombinants expressing single BDV-specific
proteins to investigate the specificity of the cytolytic
CD8+-T-cell response, revealing a major epitope on the
BDV nucleoprotein p40. In contrast, no direct evidence in favor of
the presence of in vivo relevant cytotoxic T-lymphocyte
epitopes on other BDV-specific proteins was found.
Borna disease (BD) is a persistent
viral infection of the central nervous system caused by the
single-negative-strand, nonsegmented RNA Borna disease virus (BDV)
(17). BDV has a wide host range in naturally and
experimentally infected animals and, most probably, also infects humans
(11, 13, 22), in whom it might even be detectable for long
periods in blood (20a). BDV exists of six open reading frames encoding
the nucleoprotein (p40), the phosphoprotein (p24), the glycosylated
matrix protein (p16 For experimental investigations, the rat is the most widely used animal
model. After intracerebral infection, the animals develop an
encephalomyelitis in which the infiltrating cells could be
characterized as CD4+ and CD8+ T cells and
macrophages (1, 7). BDV-specific CD8+ T cells
represent the effector cell population in the acute phase of the
disease and significantly contribute to the destruction of
virus-infected brain cells in vivo. Moreover, evidence was presented
that this T-cell population also participates in the degenerative
encephalopathy that results in severe cortical brain atrophy in the
chronic phase of the disease (2, 19, 20, 27, 28). In
addition to the immunopathological reaction caused by
BDV-specific CD8+ T cells, the same T-cell population was
shown to have beneficial effects in BD. BDV-specific CD4+ T
cells given prior to infection induce CD8+ T cells which
eliminate the virus without causing significant cell damage
(18).
The p40 and p24 proteins appear to be the most abundant proteins
produced during BDV infection. As early as 6 to 10 days after intracerebral infection of rats, p40 is detectable in the brain by
immunohistochemistry (5, 28a). Around day 15 postinfection (p.i.), p24 can be detected. Thus, the p40 protein appears to be the
protein expressed at the highest levels at early times p.i. in the
brain, followed by p24. Likewise, experimentally and naturally infected
animals first develop detectable antibodies directed against p40 and
p24 at 2 to 3 weeks p.i., whereas antibodies directed against the two
glycoproteins are not detectable before 10 to 14 weeks after infection
(12). In contrast to the humoral immune response to BDV,
little is known about the specificity of the cellular immune response
against different BDV-specific proteins. Whereas CD4+ T
cells have been induced for the p24 and p40 proteins after immunization
with purified protein (18, 20, 21), the antigen specificity
of cytolytic CD8+ T cells has never been investigated.
To determine which virus-specific antigens are recognized by cytotoxic
T lymphocytes (CTL), we made use of the following different vaccinia virus (VV)-BDV recombinants, each expressing only one BDV-specific protein: VV-BDV p40 (VV-p40), VV-BDV p24 (VV-p24), VV-BDV gp18 (VV-gp18), and VV-BDV gp94 (VV-gp94). Wild-type VV, strain WR, was used as a control. The recombinant viruses were generated by J. C. de la Torre, Scripps Research Institute, San Diego, Calif., and virus stocks were propagated by infection of BHK-21
cells at a low multiplicity of infection and virus titers were
determined on BHK-21 cells in our laboratory. Trypsin virus stocks
contained about 1 × 109 to 5 × 109
PFU/ml. The VV-BDV recombinants were used for intravenous (i.v.) infection of Lewis rats to generate a cellular immune response. The
distinct VV-BDV recombinant viruses were also used for infection of
syngeneic astrocyte target cells (F10 cells). In addition to spleen
cells from rats infected with VV-BDV recombinants, as a second source
of effector cells, lymphocytes were isolated from the brain of acutely
BDV-infected rats at 19 days p.i. to represent the in vivo situation
(19, 27). In all experiments, persistently BDV-infected F10
cells were used as target cells in cytotoxicity assays as described
previously (19).
Earlier experiments by Zinkernagel et al. (31) had indicated
that a potent cellular immune response can be induced and found in the
local lymph nodes after intra-footpad infection of Lewis rats with
wild-type VV. The immune response was dominated by major histocompatibility complex (MHC) class I-restricted CD8+ T
cells starting 3 days after infection, peaking at 5 to 7 days, and
disappearing after 10 to 12 days (31).
To generate large amounts of virus-specific T cells, female Lewis rats
were infected i.v. and immune cells were isolated from the spleen. To
evaluate the peak of the cellular immune response after i.v. VV
infection, different infectious doses of VV-BDV recombinant virus or VV
trypsin stocks ranging from 104 to 107 PFU were
injected. Six days after infection, the animals were killed, spleens
were extracted, and a single spleen cell suspension was prepared. To
determine the in vitro cytotoxicity of CD8+ T cells, spleen
cells were coincubated with 51chromium-labeled (100 µCi
of 51Cr/5 × 106 cells) persistently
BDV-infected syngeneic F10 cells, VV wild-type-infected F10 cells
(multiplicity of infection, 5), and uninfected F10 cells. At the end of
the incubation period, 50-µl aliquots of supernatant were taken and
counted in a gamma counter. Percent specific lysis was calculated by
the formula [(test release Based on these findings, in all of the succeeding experiments,
described below, effector spleen cells were harvested on day 6 from
rats infected with 107 PFU of VV or VV-BDV recombinants.
Antibodies directed against the BDV-specific proteins were detectable
after day 15 by Western blot analysis (data not shown).
We then investigated whether VV-BDV recombinants were able to
induce cytotoxic T-cell responses directed against
BDV-specific proteins. Therefore, Lewis rats were infected
with either VV-p24, VV-p40, VV-gp18, VV-gp84/94, or wild-type VV strain
WR. As shown in Table 1, effector cells
generated by VV-p40 regularly caused lysis of BDV-infected target
cells, whereas VV-p24 and VV-gp18 did not trigger cytotoxicity;
however, effector cells induced in rats after VV-gp94 infection always
had cytotoxic capacity, in one experiment (Table 1, experiment II)
causing even higher specific lysis than that of VV-p40 effectors. VV
wild-type-infected target cells were always lysed by spleen cells from
all infected rats, while no lysis was found when non-infected F10 cells
were used as targets.
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Borna Disease Virus Nucleoprotein (p40) Is a Major
Target for CD8+-T-Cell-Mediated Immune
Response
ABSTRACT
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gp18), and the glycoprotein (p57gp84 or gp94)
(4, 9, 10, 15, 24); furthermore, the BDV antigenome encodes
a protein with a molecular mass of approximately 180 kDa, which
represents the putative L-polymerase (6, 16, 23)
and the most recently identified unglycosylated p10 (26,
30).
minimal release)/(maximal release minimal release)] × 100. Rats receiving an
infectious virus dose of 107 or 106 PFU were
able to generate a cellular immune response against VV, whereas lower
infectious doses were less efficient. Furthermore, we tested the peak
activity of the T-cell-mediated immune response after i.v. infection
with VV at infectious doses of 107 or 106 PFU.
Lewis rats were killed 6 or 8 days after infection, and spleen cells
were tested for their cytotoxic activity. The CD8+-T-cell
response to VV or BDV infection was drastically decreased on day 8 p.i. in comparison to that on day 6 after infection, independent of the
infectious dose (data not shown).
TABLE 1.
Induction of cytotoxic T-cell responses to
BDV-specific proteins by VV-BDV recombinants
Since brain lymphocytes represent the relevant effector cell population
(19, 27) in the acute phase of the disease (day 19 p.i.), these cells were isolated and tested for their lytic activity on
VV-BDV recombinant virus-infected F10 cells. As shown in Table
2, this effector cell population from
BDV-infected rats was able to lyse BDV-infected F10 cells and
VV-p40-infected F10 cells but not VV-p24-, VV-gp18-, or
VV-gp94-infected F10 cells, at an effector/target cell ratio of 10:1
(Table 2, experiments I and II). To further investigate whether higher
numbers of effector cells would cause lysis of VV-p24-, VV-gp18-, or
VV-gp94-infected F10 cells, we increased the effector/target cell ratio
to 20:1 (Table 2, experiment III). To show that all target cells were infected with the different VV recombinants, spleen cells from VV wild
type strain WR-infected rats were used as controls. These effectors
lysed target cells infected with wild-type strain WR, VV-p24, VV-p40,
VV-gp18, and VV-gp94 (Table 2). This proves that all VV-BDV recombinant
viruses were infectious and in addition to VV-specific antigen should
also express the particular BDV-specific antigen. The latter was
verified by reverse transcription-PCR using p24-, p40-, gp18-, or
gp84/94-specific primer and by Western blot analyses of VV-BDV-infected
target cells, which revealed the presence of BDV-specific mRNA and
BDV-specific proteins (data not shown).
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The results demonstrate that the nucleoprotein p40 is a major target for the MHC class I-restricted cytotoxic T-cell response in Lewis rats after BDV infection. Therefore, at least one epitope recognized by BDV-specific CD8+ T cells must be located on this virus-specific protein. However, we cannot formally exclude the possibility that subdominant epitopes exist on p24, gp18, and gp84/94 of BDV. Particularly, the gp84/94 would be a candidate (Table 1); however, regarding the relevant in vivo situation as represented by brain lymphocytes, this viral protein does not appear to be a major target (Table 2). This problem of additional epitopes cannot be solved at present, since irrespective of the system used, CD8+ T cells from rats have never been successfully cultured, which would be necessary to address this question. Epitopes which are subdominant in the acute immune response may play a role in the chronic viral infection as it has been demonstrated for lymphocytic choriomeningitis virus in mice (8, 25, 29). In this respect, the moderate T-cell activity found on BDV-infected F10 cells from spleen cells of rats infected with VV-p24 or VV-gp18 (Table 1) might be unspecific or might be exerted by a few antigen-specific T cells generated against these proteins. In contrast, when we used T cells isolated from the brain of BDV-infected rats, no lysis was found on target cells expressing p24 or gp18 of BDV and only marginal lysis was found on F10 cells expressing BDV gp84/94 (Table 2, experiment 3). We did not address the question of whether fragments of p24, gp18, or gp84/94 can be processed and presented to induce CD8+ T effector cells or if these proteins are available in the appropriate amount, time frame, and place after infection, as described for other infectious systems (3, 14, 32). The BDV p40 protein is the first virus-specific antigen expressed early after infection and in considerable amounts. The fact that anti-p40 antibodies are the first virus-specific antibodies synthesized, around day 15 p.i. (17), and the fact that the p40-specific T-cell activity is also detectable early after infection make this virus-specific protein a major target antigen in both the humoral and cellular immune reaction in BD. No functional role for p40-specific antibodies has been recognized in BD so far, but as shown here, the cytotoxic T-cell immune reaction specific for the p40 protein might result in immunopathology or immunoprotection (2, 18-20, 27).
As reported earlier, the time point of the MHC class I-restricted cytotoxic T-cell response determines whether virus-infected cells are eliminated very early or whether the immune reaction proceeds to an immunopathological disease (18). Therefore, we propose that the MHC class I-restricted recognition of the BDV p40 protein represents the key event in BD development. Furthermore, the anti-p40 CD8+-T-cell response presents itself as the prime candidate for protective cellular immunity in BD.
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ACKNOWLEDGMENTS |
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This study was supported by grant from the Deutsche Forschungsgemeinschaft (Pl 256/1-1, Sti 71/2-z).
We thank Christine Rentzsch for technical support and Juan Carlos de la Torre for the generous gift of VV recombinants.
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FOOTNOTES |
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* Corresponding author. Mailing address: Institut für Impfstoffe, Bundesforschungsanstalt für Viruskrankheiten der Tiere, Paul-Ehrlich-Str. 28, 72076 Tübingen, Germany. Phone: 49 7071 967 254. Fax: 49 7071 967 105. E-mail for O. Planz: oliver.planz{at}tue.bfav.de. E-mail for L. Stitz: lothar.stitz{at}tue.bfav.de.
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Journal of Virology, February 1999, p. 1715-1718, Vol. 73, No. 2
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Copyright © 1999, American Society for Microbiology. All rights reserved.
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