1 Institute for Immunology, Ludwig Maximilians University Munich, Goethestrasse 31, 80336 Munich, Germany
2 University Claude-Bernard Lyon 1, Centre de Genetique Moleculaire et Cellulaire, Lyon, France
3 University of Ferrara, Department of Experimental and Diagnostic Medicine, Ferrara, Italy
Correspondence
Thomas Brocker
tbrocker{at}med.uni-muenchen.de
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ABSTRACT |
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Present address: The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, La Jolla, CA, USA.
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INTRODUCTION |
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Upon HSV-1 infection, innate immunity provides the first line of defence, with activated macrophages, dendritic cells (DC), NK cells and T cells as key players (Bukowski et al., 1994
; Kadowaki et al., 2000
; Kodukula et al., 1999
; Siegal et al., 1999
). Together with cytokines and the complement cascade, these cells limit the spread of epidermal infection by the herpesvirus (Ahmad et al., 2000
; Da Costa et al., 1999
; Feduchi et al., 1989
; Melchjorsen et al., 2002
). Neutralizing antibodies specific for the major envelope glycoproteins gB, gD and gH/L, as well as CD4+ and CD8+ T lymphocytes recognizing HSV antigens (Ags) can be detected after HSV-1 infection (Mikloska & Cunningham, 1998
; Mikloska et al., 1996
). Despite this HSV-specific immunity, wild-type (wt) HSV can persist life-long in the host due to different viral mechanisms that interfere with immune recognition (Fries et al., 1986
; Hill et al., 1995
; Johnson & Feenstra, 1987
; Samady et al., 2003
; Sloan et al., 2003
) and due to its ability to establish latent infections in sensory neurons.
In animal studies, the use of replication-defective HSV vaccines has been shown to induce robust and long-lived HSV-specific immunity (Morrison & Knipe, 1996, 1997
). In addition, many recombinant HSV vectors expressing foreign Ags have been developed for gene-therapeutic approaches (Huard et al., 1995
; Palmer et al., 2000
) and vaccination against bacterial (Lauterbach et al., 2004
) or viral (Hocknell et al., 2002
; Murphy et al., 2000
) infection. A major concern affecting the potential use of recombinant HSV vectors is the possible impairment of vaccine efficacy by pre-existing anti-HSV immunity. While this has been reported for adenovirus and poxvirus vectors (Etlinger & Altenburger, 1991
; Papp et al., 1999
; Parr et al., 1998
; Schulick et al., 1997
), the vaccine efficiency of poliovirus- (Mandl et al., 2001
) as well as alphavirus (Pushko et al., 1997
)-based vectors seems not to be impaired in immune hosts.
In light of the high (6090 %) prevalence of HSV-1 infection among the adult population (Cunningham et al., 2000; Stanberry et al., 2000
), it is particularly important to investigate the effect of pre-existing immunity on HSV-vaccine efficiency. It has recently been shown that upon immunization with a replication-defective HSV-1 vector, the Ag-specific antibody (Ab) response is long-lasting and not impaired by prior HSV exposure (Brockman & Knipe, 2002
). Similar results have been obtained in HSV-mediated oncolytic therapy (Chahlavi et al., 1999
). However, gene transfer into experimental brain tumours in HSV-1-seropostive mice was less efficient (Herrlinger et al., 1998
). Likewise, an HSV-1 amplicon vaccine induced immune responses that were reduced by prior infection with HSV-1 (Hocknell et al., 2002
).
Since these studies have given contradictory results concerning the inhibitory effects of pre-existing HSV-1 immunity (Brockman & Knipe, 2002; Chahlavi et al., 1999
; Herrlinger et al., 1998
; Hocknell et al., 2002
), we investigated the Ag-specific humoral and cellular immune response induced by replication-defective, recombinant HSV-1 in seropositive mice. We report that pre-existing HSV-1 immunity does substantially reduce the ability of an HSV-1-derived vaccine to induce Ag-specific humoral and cellular immune responses. Furthermore, we show that the negative impact is similar in mice infected either with homologous or heterologous HSV-1 wt strains or with a homologous replication-defective virus.
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METHODS |
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Viruses.
In order to infect mice with non-lethal doses of wt HSV-1, 2x106 p.f.u. HSV-1 KOS or strain F were injected intravenously (1x107 p.f.u. ml1 in PBS). Preparation of OVA-encoding, replication-deficient HSV-1 vaccine vectors (T0H-OVA) and green fluorescent protein (GFP)-encoding control vectors (T0-GFP) has been described previously (Lauterbach et al., 2004). These vectors harbour deletions in three immediate-early genes (ICP4 and ICP27, which are essential for virus replication, and ICP22). lacZ was inserted into the UL41 locus, which led to a disruption of this gene, which encodes the virus host shut-off (vhs) protein. For recombinant HSV-1 (rHSV-1) vaccination, frozen virus stocks were thawed on ice, and diluted in PBS to 4x106 rHSV-1 (200 µl)1 for intravenous (i.v.), intraperitoneal (i.p.) and subcutanous (s.c.) injection, and to 4x106 rHSV-1 (50 µl)1 for intradermal (i.d.) injection. Before injection, virus suspensions were sonicated in a water bath for 5 s.
Adoptive transfer.
OT-1 CD8+ T cells were prepared from lymph nodes and spleens of transgenic mice. Briefly, spleen and lymph nodes were taken out, and single-cell suspensions were prepared. Erythrocytes were removed by osmotic lysis, and after determining the percentage of TCR-transgenic T cells by flow cytometry, 1x106 transgenic T cells were injected intravenously into recipient mice.
Enzyme-linked immunosorbent assay (ELISA).
For the detection of OVA-specific antibodies, 96-well microtitre plates (Nunc Maxisorp) were coated with 15 µg chicken OVA ml1 (Sigma Chemicals Co.) at room temperature overnight. For the detection of anti-HSV antibodies, plates were either coated with T0-GFP in PBS (2x105 p.f.u. ml1) overnight at 4 °C or with HSV-1 MacIntyre viral lysate (tebu-bio GmbH) under the same conditions. Plates were blocked (PBS, 0·5 % milk powder and 0·05 % NaN3), and immune sera (diluted 1 : 100 in blocking buffer) were incubated for 2 h at room temperature. After washing five times with PBS, HRP-labelled second-step goat sera specific for mouse IgG (Serotec) in PBS, 0·5 % milk powder, 0·05 % Tween 20, were added and incubated for 2 h. After five washing steps, the amount of bound Ab was determined by the addition of substrate solution (1 mM 3,3',5,5' tetramethylbenzidine, 0·3 µl ml1 30 % H2O2, in 0·2 M potassium acetate). The reaction was stopped by the addition of 2 N H2SO4, and the A450 was determined with a Vmax-microplate reader (Molecular Devices Corporation).
Monoclonal antibodies, tetramers and flow cytometry.
Lymphocytes were analysed using the monoclonal antibody (mAb) anti-CD8a-APC (Ly2) from Caltag (Burlingame, CA). Analytic flow cytometry was performed on a FACScalibur (Becton Dickinson), and the data were analysed using Cellquest software (Becton Dickinson). H-2Kb/OVA257-264-phycoerythrin (PE) and H-2Kb/gB498-505-tetramer-PE complexes were purchased from ProImmune Limited.
In vivo cytotoxic T-lymphocyte (CTL) assay.
This assay was performed as published previously (Kleindienst et al., 2005). Syngeneic C57BL/6 spleen and lymph-node cells were depleted of erythrocytes by osmotic lysis. Cells were washed and split into two populations. One population was pulsed with 106 M OVA257-264-peptide for 1 h at 37 °C, washed and labelled with a high concentration of carboxy-fluorescein diacetate succinimidyl ester (CFSE, 2·5 µM) (CFSEhigh cells). The second control population was labelled with a low concentration of CFSE (0·25 µM) (CFSElow cells). For i.v. injection, an equal number of cells from each population (CFSEhigh and CFSElow) was mixed, such that each mouse received a total of 2x107 cells. Cells were injected into vaccinated mice. Twenty hours later, mice were sacrificed and spleen and lymph nodes removed. Cell suspensions were analysed by flow cytometry; approximately 5x105 CFSE-positive cells were collected for analysis. Peptide-pulsed and non-pulsed target cells were recognized according to their different CFSE intensities. To calculate specific lysis, the following formulae were used: ratio=(percentage CFSElow/percentage CFSEhigh); percentage specific lysis=[1(ratio unprimed/ratio primed)x100].
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RESULTS |
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OVA-specific humoral responses are reduced or inhibited completely in HSV-seropositive mice
It has been shown elsewhere that induction of long-lasting specific Ab responses after immunization with HSV vectors is possible, even in the presence of anti-HSV antibodies (Brockman & Knipe, 2002). To test the ability of T0H-OVA to induce an OVA-specific Ab response in HSV-seropositive animals, we infected mice with T0-GFP by the i.v. or s.c. route (Fig. 1a and b
), since replication-defective HSV-1 mutants have already been shown to induce antiviral immunity (Farrell et al., 1994
; Geiss et al., 2000
; Morrison & Knipe, 1994
). The injection routes were chosen according to results obtained by infecting mice via different routes (data not shown). i.v. and s.c inoculations were performed in order to induce high and low anti-HSV-1 Ig titres, respectively. The seroconversion was verified by measuring anti-HSV Ab titres in the serum of infected mice 2 and 4 weeks after T0-GFP infection. In two independent experiments, we could confirm our previous observations that low levels of anti-HSV-1 IgG were obtained via the s.c. route, while i.v.-inoculated animals produced high levels of HSV-specific Ab (Fig. 1b, e
). Four weeks post-infection with T0-GFP, we vaccinated mice with T0H-OVA by the s.c. (Fig. 1a, b, c
) or i.v. (Fig. 1d, e, f
) route. In both experiments OVA-specific IgG titres could be detected at 2 weeks after T0H-OVA immunization in naive control animals (Fig. 1c, f
, 6 weeks post-infection). However, in HSV-seropositive mice, the detectable OVA-specific Ab titres were inversely proportional to pre-existing HSV-specific Ab titres: mice immunized by the s.c. route with T0H-OVA (Fig. 1a, b, c
) could not mount an OVA-specific humoral response, even if pre-existing immunity created high (via i.v. inoculation) or lower (via s.c. inoculation) titres of HSV-specific Ab. In contrast, seropositive mice vaccinated by the i.v. route with T0H-OVA still mounted a weak anti-OVA IgG response (Fig. 1f
). The reduction was stronger in mice that received i.v. T0-GFP and had higher anti-HSV serum titres than animals with lower anti-HSV titres (Fig. 1e, f
). These results indicate that humoral responses to an HSV-1-vector-encoded Ag are affected in HSV-1-seropositive animals.
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Nineteen days after T0-GFP infection, all OT-1>RIP-OVAlo mice were immunized by the i.v. route with T0H-OVA and monitored for the development of diabetes as a direct read-out for in vivo induction of efficient CTL responses (Fig. 3a). In the non-infected, seronegative group, all mice became diabetic after 56 days. Also, in the group of mice that was s.c.-inoculated and showed relatively modest anti-HSV Ab titres, 66 % of the mice became diabetic. In mice that had received i.d. or i.p. T0-GFP, only one mouse per group could be considered as diabetic at various days (open triangles and filled squares, respectively). In contrast, vaccination with T0H-OVA did not induce diabetes in previously i.v.-infected mice. In order to see whether the amount of anti-HSV IgG correlated with the grade of inhibition of the vaccine, we analysed IgG titres in relation to the number of diabetic mice (Fig. 3b
shows as an example the data from day 9 after T0H-OVA immunization. Data from other time points show similar results). This graph (Fig. 3b
) demonstrates that the efficacy of T0H-OVA immunization is negatively correlated to the magnitude of anti-HSV Ab titres, in other words, pre-existing anti-HSV immunity diminishes the efficacy of a second immunization with a homologous recombinant virus.
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These data clearly demonstrate that despite the inherent immune evasion strategies of HSV-1, infection with wt HSV-1 induces strong antiviral immune responses and interferes significantly (P<0·005 KOS versus PBS and P<0·005 strain F versus PBS; Fig. 4e) with the efficacy of a replication-defective, recombinant HSV-1 vaccine vector. In addition, our data demonstrate that pre-existing HSV-specific immunity interferes in a similarly effective manner with subsequently applied analogous vaccines, even if it has been elicited by replication-competent HSV strains (HSV-F and HSV-KOS) or replication-defective HSV-based viral vectors (T0-GFP) (P>0·05 KOS versus T0-GFP and P>0·05 strain F versus T0-GFP; Fig. 4e
).
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DISCUSSION |
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Recently, we demonstrated that systemic (i.v.) injection of a recombinant, replication-defective HSV-1 mutant induces strong CD8+ T-cell responses that provide protection against infection with a recombinant intracellular bacterium, L. monocytogenes (Lauterbach et al., 2004). The partly contradictory results in the literature concerning the influence of pre-existing host immunity on vector efficiency (Brockman & Knipe, 2002
; Chahlavi et al., 1999
; Herrlinger et al., 1998
; Hocknell et al., 2002
) led us to investigate this question for the recombinant vector described previously (Lauterbach et al., 2004
). We could demonstrate clearly that pre-existing anti-HSV immunity reduced humoral (Fig. 1
) and cellular (Figs 2
, 3
and 4
) immune responses against the vaccine-encoded Ag.
Vaccination with a replication-defective vhs HSV-1 mutant strain has been shown to elicit strong antiviral IgG responses and to protect mice against challenge with wt HSV-1 (Geiss et al., 2000). Thus, in order to induce seroconversion, we first infected mice with a homologous replication-defective HSV-1 strain. We could show that the strength of anti-viral Ab responses was highly dependent on the injection route (Figs 1b, e
and 3b
). However, even low anti-HSV IgG titres completely abolished anti-OVA IgG responses after immunization with T0H-OVA (Fig. 1c
) or reduced them about three- to sixfold (Fig. 1e
). Since we had previously shown that T0H-OVA is a relatively weak inducer of OVA-specific Ab responses (Lauterbach et al., 2004
), these results were not unexpected. A further reduction of vaccine units' by pre-existing antiviral immune responses probably leads to an insufficient amount of OVA production, which is essential for inducing humoral responses, because OVA protein is not a structural part of the virus particle itself. Similar results were obtained in a HSV-amplicon study, in which HIV Env-specific humoral immune responses were undetectable in pre-infected mice (Hocknell et al., 2002
).
Since our vaccine vector was mainly designed for the induction of strong CD8+ T-cell responses, the results shown in Figs 24
seem to be of greater importance. The expansion (Figs 2
and 4d
) and CTL effector function (Figs 3a
, and 4e
) of OVA-specific CD8+ T cells were largely diminished in HSV-seropositive mice. The inhibition of functional CTL responses could be correlated with the magnitude of anti-HSV IgG titres (Fig. 3b
). These observations are in accordance with previous studies that demonstrate a dominant role for immune serum in mediating prophylactic protection against HSV-1 infection (Keadle et al., 2002
). The in vivo assay used as readout in Fig. 3
measures the rise of urine glucose concentration as a consequence of fully activated TCR-transgenic CD8+ T cells that lyse OVA257-264-presenting
-islet cells in RIP-OVAlo mice. The failure to induce diabetes in pre-infected mice with high antiviral IgG titres (Fig. 3
) does not rule out a partial activation and thus expansion of OVA257-264-reactive T cells, as shown in Figs 2(b)
and 4(d)
for endogenous CD8+Tet+ T cells. These data are in accordance with the findings of Hocknell et al. (2002)
who described a 4060 % reduction of cellular immune responses in pre-infected mice after in vitro restimulation. The stronger inhibitory effects in our experiments might reflect the differences of in vivo versus in vitro assays. It is most probable that the low number of CD8+Tet+ T cells detected after vaccination of pre-infected animals (Figs 2b
and 4d
) would show effector functions after in vitro restimulation. However, when we tested the effector functions directly in vivo (Fig. 4e
), the 90 % reduction in CTL activity observed in HSV-F or HSV-KOS pre-infected mice reflected a grade of inhibition close to complete vaccine neutralization (Fig. 4e
).
An ICP8 HSV-1 strain encoding -galactosidase (HD-2 virus) was shown to induce similar Ag-specific IgG responses whether injected into naive or HSV-1-seropositive mice (Brockman & Knipe, 2002
). The discrepancy between these and our results probably reflects the differential grade of genetic crippling of the two vaccine vectors: ICP4, ICP22, ICP27 and vhs (this study) versus ICP8 only (Brockman & Knipe, 2002
), respectively. ICP8 mutants still synthesize the whole spectrum of HSV gene products that are expressed independently of virus replication, but infected cells do not produce new virus (Littler et al., 1983
; Morrison & Knipe, 1994
; Wu et al., 1988
). Thus, this vector still has the means to modify cell metabolism in favour of its own gene expression. This could be achieved, among other strategies, through blocking of RNA splicing by ICP27 (Hardy & Sandri-Goldin, 1994
), sustaining protein synthesis through ICP34·5 (Cassady et al., 1998
), or the inactivation of CTLs (Sloan et al., 2003
) and blocking of apoptosis (Ogg et al., 2004
) by the US3 kinase. In cells infected with a mutant lacking the immediate-early genes ICP4, ICP22 and ICP27, only production of ICP6, ICP0, ICP47 (which is not effective in rodents) and OrfP is to be expected. Furthermore, the model-Ag
-galactosidase in the HD-2 virus was fused to the N terminus of a truncated ICP8 (Brockman & Knipe, 2002
). Thus, the Ag is expressed as an integral part of the virus genome, whereas the Ag in our vector was driven by the hCMV promoter. The Ag expression might therefore be higher in HD-2-infected cells than in T0H-OVA-infected cells. This, however, remains speculative, because the vaccines were not directly compared.
Taken together, our data could suggest that an HSV-1-based vaccine vector that is adapted for high safety (ICP4, ICP22, ICP27 and vhs) also shows a higher sensitivity towards inhibition by pre-existing host immunity, whether induced by prior immunization or natural infection. With regard to future applications, it has to be remarked that Ag-specific CD8+ T-cell responses were inhibited but not fully abolished (Figs 2b and 4d, e
; Hocknell et al., 2002
). The OVA-specific CD8+ T-cell expansion in T0-GFP-treated mice was not stronger than that of wt HSV-1 pre-infected mice (Fig. 4d
) that had higher HSV-specific IgG levels (Fig. 4b
) and higher frequencies of HSVgB-reactive CD8+ T cells (Fig. 4c
). Similarly, the observed differences in CTL effector function between all pre-infected groups were not statistically significant (P>0·05).
Thus, after the adaptive immune response has reached a certain level of protection against HSV, it apparently cannot be boosted further. This demonstrates nicely the limited effectiveness of the immune system against infection with HSV-1, so that even replication-defective HSV-1 mutants (and also HSV-1 amplicons; Hocknell et al., 2002) still have the potential to infect cells in an immune animal, even though to a much lesser extent. Accordingly, in several vaccine studies in rodents, both the replication of virulent challenge HSV-1 and disease severity were decreased, but infection per se was not prevented (Geiss et al., 2000
; Morrison & Knipe, 1994
). The mouse immune system is probably sufficient to keep the virus in check when few cells are infected. In humans, however, the natural host of HSV-1, the highly adapted virus might escape the adaptive immune response through the action of its immune-evasion genes, so that even relatively low amounts of virus can cause disease. This is in accordance with the fact that so far no anti-HSV vaccine candidate has been shown to be efficacious in clinical trials [reviewed by Deshpande et al. (2000)
]. Besides, in humans, HSV-specific Ig titres are only high directly after infection or reinfection [reviewed by Koelle & Corey (2003)
].
What is very unfortunate on the one hand, namely the failure to vaccinate against HSV, offers on the other hand the possibility to use HSV-derived vectors for gene therapy or vaccination, despite the high prevalence of this virus in the human population. Of course, we are aware of the limitation of the mouse model in the case of HSV-1, but in summary, all data argue for a reduced but not abolished immune response after vaccination with a recombinant HSV-1 vector. Thus, an immunization protocol with several injections or a heterologous prime-boost protocol, as shown by Wang et al. (2003), might provide promising options for safe HSV-1-based vaccines. In addition, efforts should be made in the future to optimize HSV-1-vector backbones in a way such that safety issues do not completely attenuate the intrinsic immune-evasion mechanisms of HSV-1. This last feature might turn out to be particularly advantageous to render HSV-1-based vaccines more efficient in the cases of pre-existing immunity and of serial applications.
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ACKNOWLEDGEMENTS |
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Received 13 April 2005;
accepted 14 June 2005.
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