1 Génétique des Virus, Institut Cochin (INSERM U567, CNRS UMR8104), 22 rue Méchain, 75014 Paris, France
2 UMR INRA-ENVA-AFSSA 1161 de Virologie, Ecole Nationale Vétérinaire d'Alfort (ENVA), 7 rue du Général de Gaulle, 94704 Maisons-Alfort, France
Correspondence
Pierre Sonigo
sonigo{at}cochin.inserm.fr
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ABSTRACT |
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Present address: UMR INRA-ENVA-AFSSA 1161 de Virologie, ENVA, 7 rue du Général de Gaulle, 94704 Maisons-Alfort, France.
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INTRODUCTION |
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Live vaccines against human AIDS, although promising in terms of efficacy, have raised major concerns over safety, due to the possibility of reversion to virulence or pathogenicity in particular host contexts (reviewed by Mills et al., 2000). Unfortunately, genetic modifications aimed at diminishing the pathogenic potential of such vaccines have resulted in parallel reduction in protective efficacy (Denesvre et al., 1995
; Johnson et al., 1999
; Wyand et al., 1999
). Additional targets for mutagenesis that allow optimization of the balance between the efficacy and safety of live-attenuated vaccines must therefore be identified. Most genetic targets investigated thus far have affected virological functions. We wished to address the possibility of improving live-attenuated vaccines by modifying immunological properties and, in particular, the immune response elicited by an immunodominant virus epitope.
Whilst some immune responses elicited by vaccination against lentiviruses contain virus replication, other deleterious responses may actually enhance lentivirus dissemination in immunized animals following virulent challenge (Hosie et al., 1992; Huisman et al., 1998
; Karlas et al., 1998
, 1999
; Lombardi et al., 1994
; Richardson et al., 1997
, 2002
; Siebelink et al., 1995
; Wang et al., 1994
). The induction of such immune responses, by offsetting the benefit afforded by protective responses, may be a confounding factor in the development of vaccines against lentivirus diseases. Many instances of immune-mediated enhancement of infection have been attributed to antibodies that enhance virus infectivity (Fust, 1997
; Sullivan, 2001
). It may thus be of interest to study live-attenuated viruses or subunit vaccines bearing modifications in the domains potentially recognized by enhancing antibodies (Eaton et al., 1994
; Homsy et al., 1989
, 1990
; Robinson et al., 1990a
, b
, 1991
; Takeda et al., 1988
; reviewed by Fust, 1997
). An attractive candidate for such an approach is the principal immunodominant domain (PID). The PID, found in the extracellular portion of the transmembrane glycoprotein (TM) of all lentiviruses, is highly conserved as regards amino acid sequence among isolates of a given lentivirus and strongly immunogenic (Bertoni et al., 1994
; Chong et al., 1991
; Fontenot et al., 1992
; Gallaher et al., 1989
; Oldstone et al., 1991
; Pancino et al., 1993a
). Moreover, mAbs directed against the PID have enhanced in vitro propagation of HIV type 1 (HIV-1) in several different cell types (Eaton et al., 1994
; Homsy et al., 1989
, 1990
; Robinson et al., 1990a
, b
, 1991
; Takeda et al., 1988
). We have shown previously that, despite its high degree of conservation, the PID of both HIV-1 and FIV may be modified extensively without loss of virological function, i.e. envelope-mediated membrane fusion and replicative capacity in transformed cell lines. Nevertheless, such modification substantially diminished binding by antibodies directed against native PID (Merat et al., 1999
; Pancino & Sonigo, 1997
). Therefore, modification of the PID, by precluding induction of potentially enhancing antibodies, may provide a means of improving the immunological quality of lentivirus-based vaccines. Moreover, this strategy would provide a convenient marker, detected readily by serological analysis, for differentiating natural infection from vaccination. Similarly, this modification would allow the vaccine and challenge strains to be distinguished in vaccine trials.
The Petaluma strain of FIV (FIVPet) (Pedersen et al., 1987; Talbott et al., 1989
), once adapted for propagation in transformed cell lines, exhibits attenuated pathogenicity (Dow et al., 1999
; Pistello et al., 1999
). In a recent vaccine trial, cats vaccinated with the FIVPet strain were protected from superinfection with a heterologous strain (FIVM2) from the same clade (Pistello et al., 2003
). In a previous study, a large set of recombinant viruses bearing random mutations in the PID were generated from a molecular clone, 34TF10, of the FIVPet strain (Pancino & Sonigo, 1997
) and characterized in continuous cell lines. In the present study, we have addressed the role of the PID in the course of in vivo infection. To this end, cats were infected with two viruses, TN14 and TN92, shown previously to replicate efficiently in Crandell's feline kidney (CrFK) cells and to escape recognition by antibodies against the parental immunodominant epitope (Pancino & Sonigo, 1997
). The potential utility of these recombinant viruses as vaccines was also evaluated subsequent to virulent challenge with the heterologous strain Wo (FIVWo), which belongs, like the Petaluma strain, to clade A. FIVWo, which has only been passaged in primary feline lymphocytes, has been shown to be pathogenic for cats (Moraillon et al., 1992
).
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METHODS |
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Immunization and challenge.
Four groups of five 2-month-old specific pathogen-free cats (IFFA-CREDO) were inoculated intraperitoneally with 1000 TCID50 of the parental 34TF10 virus (group A) or the PID-mutant viruses TN14 and TN92 (groups B and C, respectively). Group D received filtered supernatants of uninfected CrFK cells. One year later, all cats were challenged intraperitoneally with 10 50 % cat infectious doses (CID50) of the primary and pathogenic strain FIVWo. This strain differs from FIVPet, but belongs to the same clade. In particular, Gag and Env sequences of the vaccine and challenge strains differ at 4 and 10·2 % of amino acid residues, respectively (Pancino et al., 1993b).
Assays for anti-Env and anti-p17 antibodies.
The humoral anti-Env response was assessed by ELISA using peptides corresponding to an immunogenic domain (TM2) of the TM envelope glycoprotein comprising the PID sequence (Pancino et al., 1993a). TM2 peptides comprising either the wild-type PID sequence (YQELGCNQNQFFCKV) or the modified PID sequence of the TN14 (YQELGCEHQHFFCKV) or TN92 (YQELGCRPAAFFCKV) viruses were synthesized and cyclized by creation of a disulfide bond between the two cysteines (Neosystem Laboratory and Synt : em), so as to enhance the sensitivity of the test. The anti-Gag response was assessed by ELISA using recombinant Gagp17 expressed as a glutathione S-transferase fusion protein (Reid et al., 1991
) as described previously (Avrameas et al., 1993
; Richardson et al., 1997
).
Neutralization assay.
The capacity of feline sera to neutralize infectivity of FIVWo for feline PBMCs was evaluated as described elsewhere (Richardson et al., 1998). All sera were heat-inactivated at 56 °C for 30 min and sterilized by filtration (0·22 µm). For each cat, sera collected before immunization and on the day of challenge were tested at a final dilution of 1/20. Final dilutions of virus stock were 1/40, 1/100, 1/200, 1/400 and 1/2000.
Preparation of plasma RNA.
Plasma was filtered (0·45 µm pore-size filter in SpinX tubes; Merck Eurolab) and cell-free RNA was extracted from 140 µl plasma in duplicate by using commercially available materials (Viral RNA Mini kit; Qiagen) and eluted in 2x40 µl elution buffer according to the manufacturer's instructions. Aliquots of RNA were stored at 80 °C.
Quantification of viral load.
Plasma viral load was measured by real-time quantitative RT-PCR. A conserved region of the gag gene of FIV was selected as the target sequence for RT-PCR. Amplification of wild-type template yielded a product of 311 bp, corresponding to nt 7711081 of the 34TF10 molecular clone (GenBank accession no. NC_001482; Talbott et al., 1989).
(i) Synthesis of RNA standard.
To synthesize the RNA standard, a DNA template was amplified by PCR from a plasmid (pKSgag) containing the entire gag sequence of the FIVWo strain (Pancino et al., 1993b). The 5'-primer sequence, 5'-TAATACGACTCACTATAGGGCGAATT-3', corresponded to nt 626651 of the pKSgag plasmid and the promoter sequence for T7 RNA polymerase (underlined) as proposed by Zhang et al. (1997)
. The 3'-primer sequence, 5'-ACCATAGTTGAACTTCCTCACCT-3', corresponded to nt 11241146 of the 34TF10 sequence. pKSgag (10 ng) was amplified by PCR in a final reaction volume of 50 µl containing 1·5 mM MgCl2, 200 µM each dNTP, 1x commercial buffer, 2·5 U Taq polymerase (Life Technologies) and 0·4 µM each primer. DNA was denatured at 94 °C for 5 min, subjected to 30 amplification cycles (94 °C for 30 s, 54 °C for 30 s, 72 °C for 30 s) and elongated at 72 °C for 7 min. The PCR product was purified by absorption on a silica column (Nucleospin Extract kit; Machery Nagel). Standard RNA was synthesized as the runoff transcription product of the purified PCR product by using T7 RNA polymerase (RiboMax Large Scale RNA Production system T7; Promega). DNA template was hydrolysed with RQ1 RNase-free DNase (Promega). Standard RNA was purified by absorption on a silica column (RNeasy Mini kit; Qiagen) and quantified by measurement of A260. Standard RNA was aliquotted and stored at 80 °C.
(ii) Quantitative RT-PCR.
Quantitative real-time RT-PCR was performed in one step with a LightCycler RNA Master Hybridization Probes kit (Roche Diagnostics), using a LightCycler instrument (Roche Diagnostics) according to the manufacturer's instructions. FIV primers, 0771f and 1081r, and Taqman probe, 1010p, have been described by Klein et al. (1999). In each glass capillary, the 20 µl RT-PCR mixture contained 3·25 mM Mn(OAc)2, 1x Tth reaction buffer, 500 nM each primer, 200 nM TaqMan probe and 5 µl standard or sample RNA. After reverse transcription for 30 min at 61 °C, the template was denatured for 4 min at 95 °C and amplified for 45 cycles of 10 s at 95 °C and 60 s at 60 °C. Samples were then quantified with the LightCycler quantification software version 3.35 (Roche Diagnostics) by comparison with a standard curve prepared by amplification of 10-fold dilutions of standard RNA (ranging from 5 to 500 000 copies per capillary). Dilutions of RNA standard were made in RNA-free water containing 10 ng carrier RNA µl1 (MS2 RNA; Roche Diagnostics). The sensitivity of this technique was 700 copies (ml plasma)1.
Detection of virus DNA.
Twenty-nine weeks after inoculation of cats with the 34TF10 or PID-mutant viruses, PBMCs were isolated from blood on Ficoll gradients (Abcys Valbiotech). Genomic DNA was isolated from 1x106 PBMCs by using commercially available materials (QiaAmp DNA Blood Mini kit; Qiagen) according to the manufacturer's instructions. DNA was eluted in 2x100 µl elution buffer. Conserved regions of the gag and env genes of FIV were selected as target sequences for amplification. Nested PCR of the gag gene has been described previously (Richardson et al., 1997). Semi-nested PCR of the env gene was performed by using the external primers SpeNew (5'-CATCAAGTACTAGTAATAGGATTAAA-3') (82778302) and ASNde (5'-GATTTGATTCGAAATGGATTCATATGAC-3') (89018928) and the semi-nested primers SpeNew and NdeWo (5'-GATTCATATGACATACCTTCCTCAAAG-3') (88868912). For the first amplification, complete reactions contained 200 µM dNTPs, 1·5 mM MgCl2, 300 nM each primer, 1x commercial buffer and 2·5 U Taq polymerase (Life Technologies) in a final volume of 100 µl. For the semi-nested amplification, 2 µl aliquots of the first amplification products were transferred to 98 µl of a reaction mix similar to the mix used for the first amplification, but with 600 nM of each primer. PCR was performed by using the GeneAmp 9600 PCR system (Perkin-Elmer). DNA was denatured at 94 °C for 5 min, subjected to 28 cycles of amplification (94 °C for 30 s, 50 °C for 30 °C, 72 °C for 30 s) and finally elongated at 72 °C for 7 min. For each cat, reactions were first performed with 500 ng genomic DNA. When the results of PCR were negative, reactions were repeated with 1 µg DNA. Amplification products (10 µl) were subjected to electrophoresis on 2·8 % agarose gels.
Analysis of PID sequence after inoculation of PID-mutant viruses.
To determine whether the selection of reverse mutations had taken place in cats inoculated with viruses bearing a modified PID, PID sequences were determined 29 weeks after inoculation for each cat of the two groups inoculated with PID-mutant viruses. Amplification products obtained by nested PCR of the env gene as described above were sequenced by using the ABI 373 Stretch system (PE Applied Biosystems). Amplification products were cloned and five clones per cat were analysed.
Distinction of FIVWo and FIVPet by differential restriction-enzyme digestion.
Virus RNA was extracted from plasma as described above and subjected to RT-PCR. The target sequence was selected so as to contain restriction-enzyme sites unique to 34TF10 or FIVWo amplicons, and corresponded to a portion of the env gene comprising the PID. For synthesis of complementary DNA, 2·5 µl RNA sample was diluted 1 : 1 with buffer containing 10 mM Tris/HCl (pH 7·5), 1 mM dithiothreitol (DTT), 100 µg BSA ml1 and 0·04 U RNasin µl1 (Promega). RNA was denatured at 65 °C for 5 min and placed immediately on ice. A reverse-transcription mix (15 µl) was added so as to yield 0·3 U random hexamers ml1 (Pharmacia), 0·5 mM dNTPs, 10 mM DTT, 1x commercial buffer and 100 U Superscript II (Life Technologies) in a final volume of 20 µl. Reaction mixtures were held at 25 °C for 10 min to promote primer annealing and then incubated at 42 °C for 50 min. RT was inactivated by incubation at 95 °C for 5 min. Highly conserved sequences were selected for primer sites. cDNA was amplified by nested PCR. External primers were EnvXbaIS613 (5'-GACTTTCTTGGGGCAATGATAC-3') (68826903) and EnvXbaIR957 (5'-ATCAGTGGGATTTGTAATGGGTCT-3') (72267249). Nested primers were EnvXbaIS624 (5'-GGCAATGATACATCTAAAAGCTA-3') (68936915) and EnvXbaIR896 (5'-CATTTTTCCTCCTGTTAGACATA-3') (71657187). PCR was performed essentially as described for detection of virus DNA by nested PCR in the env gene, except that the concentrations of primers were 200 and 400 nM for the first and nested amplifications, respectively, and the annealing temperatures were 51 and 50 °C for the first and nested amplifications, respectively. Amplification products (10 µl) were then digested either with BsmAI (specific for the 34TF10 amplicon) or with XbaI (specific for the FIVWo amplicon). Digestion fragments were separated by electrophoresis on 2 % agarose gels.
Enumeration of CD4+ and CD8+ cells.
PBMCs were isolated at different times after challenge as described above and resuspended in fetal calf serum (FCS) plus 10 % DMSO (Sigma). PBMCs were then frozen at 80 °C in ampoules immersed in 2-propanol, so as to allow gradual cooling, and stored in liquid N2 until use. For enumeration of T cells, cells were thawed, resuspended in RPMI 1640 medium containing 10 % FCS, 100 IU penicillin ml1 and 100 µg streptomycin ml1 (Life Technologies) and incubated at 37 °C overnight. Cells were washed once with PBS and once with PBS plus 2 % FCS, and then incubated at 4 °C for 45 min in the dark with 50 µl mouse anti-feline CD4fluorescein isothiocyanate and mouse anti-feline CD8phycoerythrin (PE) (both from Southern Biotechnology Associates) diluted 150- and 300-fold, respectively. Negative controls consisted of cells incubated with 10-fold-diluted mouse IgG1PE antibody (Immunotech). Cells were then washed twice in PBS plus 2 % FCS and fixed in 1 % paraformaldehyde for 10 min. Cells were resuspended in 0·5 ml PBS and counted by using an EPICS XL flow cytometer with the System II 3.00 software (Beckman Coulter).
Statistical analysis.
Analyses were performed by using the NCSS software (DeltaSoft). Analysis of variance on repeated measures were performed on viral load throughout the follow-up in order to test the interactions between the different parameters (groups, cats, days). The NewmanKeuls multiple-comparison test was used to determine the groups that differed significantly. Significant differences were confirmed by comparison of cumulative area under the curve with a KruskalWallis test.
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RESULTS |
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Vaccination with 34TF10, TN92 and TN14 viruses diminished infection with the virulent challenge strain
(i) Viral load.
After challenge, cats preinfected with 34TF10 or PID-mutant viruses displayed a delayed and globally reduced viral load, fewer than 104 FIV RNA copies (ml plasma)1 on average, whereas control cats exhibited higher RNA levels, often exceeding 5x105 RNA copies (ml plasma)1 (Fig. 4). Moreover, in both groups infected with PID-mutant viruses, virus RNA was undetectable after challenge at all time points examined in one of five cats. The analysis of variance on repeated measures revealed a significant difference between the control group and the vaccinated groups (P=0·009). This difference was confirmed by the comparison of areas under curves (P=0·014). The vaccinated groups were not equivalent as regards viral load. Analysis of the number of cats presenting fewer than 5x103 copies (ml plasma)1 at every time point revealed a significant difference between the TN92 group and the other groups (P=0·0079), suggesting that cats vaccinated with the TN92 virus contained virus replication better than cats in other groups.
(ii) Distinction of FIVPet and FIVWo strains.
After challenge by FIVWo, restriction-fragment length-polymorphism analysis was used to distinguish FIVWo and 34TF10 (Fig. 5). Plasma virus RNA was amplified, when plasma viral load allowed, at two different time points, once shortly after challenge and once at a later time. After challenge with FIVWo, all cats became superinfected with FIVWo, as evidenced by analysis of plasma virus RNA (Table 2
). The live-vaccine strains were detected at the later date only in four cats, three (Norme, Noria and Normande) in the TN92 group and one (Noblesse) in the TN14 group. For Noblesse, Noria and Normande, FIVWo had been also detected in plasma on days 105, 180 and 236 after challenge, indicating that the strains coexisted in these infected cats.
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(iv) Stability of CD4+ and CD8+ T-cell populations for 2 years after virulent challenge.
Peripheral blood CD4+ and CD8+ T cells were enumerated at four dates after challenge with FIVwo: the day of challenge and days 35, 342 and 725 (Table 3). No differences were observed between the groups, even as late as 2 years after virulent challenge. Judging, however, by the stability of the CD4+ population in unvaccinated control cats, infection had not progressed beyond the asymptomatic stage at this time.
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DISCUSSION |
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Previous studies have shown that the PID of FIV and HIV-1 can be modified with retention of envelope function in vitro (Merat et al., 1999; Pancino & Sonigo, 1997
). We now show that such is also the case in vivo as, following inoculation with the two PID-mutant viruses, the course of infection was similar to that of the parental virus, 34TF10. Admittedly, however, as 34TF10 itself gives rise to an attenuated infection in vivo, further reduction in viral load resulting from modification of the PID may have been difficult to appreciate. Nevertheless, few reversions were observed in the PID sequence after inoculation with modified viruses. Taken together, these observations the infectivity of modified viruses in vivo and the low frequency of reversion suggest that substitutions in the PID are tolerated well in vivo, in apparent contradiction to the high level of conservation of the canonic PID sequence in natural FIV isolates. Selection for variation in epitopes under immunological pressure being well-documented, it is tempting to speculate that the converse phenomenon, i.e. conservation of epitopes whose cognate immune response favours virus propagation, might also take place.
Modification of the PID altered the immunogenicity of envelope glycoproteins. The TN14 virus elicited antibodies that bound strongly to the cognate modified PID but poorly to the wild-type PID, whereas the TN92 virus elicited antibodies that bound poorly to both cognate and wild-type PID sequences. Whilst, like the parental 34TF10 virus, both modified viruses afforded partial protection against virulent challenge, viral load appeared lower in cats vaccinated with the TN92 virus than in cats vaccinated with the parental or TN14 virus. We might speculate that the strong antibody response elicited by the native PID ordinarily diverts the immune response away from protective epitopes and that the diminished immunogenicity of the PID of the TN92 virus promoted responses against these less immunogenic epitopes. In the same sense, in vaccination of macaques against SIV, protection afforded by a subunit vaccine composed of envelope glycoproteins was abolished by a boost with a peptide containing the PID (Mitchell et al., 1995).
Following challenge of vaccinated cats with FIVWo, the challenge strain was predominant. Thus, whilst live vaccines did not afford complete protection against superinfection, vaccinated cats contained infection better than the control cats. Similar observations have been made as regards vaccination of macaques and cats with attenuated strains of SIV and FIV, respectively (Khatissian et al., 2001). In the SIV study, however, the challenge strain was highly similar to the vaccine strain. Our trial shows, in the FIV model, that a substantial level of protection can be achieved against a heterologous challenge.
In a previous study, Pistello et al. (1999) observed that vaccination with FIVPet afforded partial protection against challenge with the primary strain FIVM2 evident from 2 years after challenge, but not in earlier stages. In a more recent study (Pistello et al., 2003
), the same authors confirm the safety and vaccinal efficacy of an attenuated vaccine derived from FIVPet by long-term culture. Here, protection afforded by live vaccines against the primary isolate FIVWo was already manifest during primary infection. We have not, for the moment, addressed the issue of protection against disease, which will require long-term observation. Nevertheless, reduction in viral load in the early stages of infection is associated strongly with improved outcome in vaccination against lentiviruses (Diehl et al., 1996
; Reimann et al., 1999
; Verhofstede et al., 1994
).
Modification of the PID appears to provide a means of improving live-attenuated vaccines against lentivirus infection. Nevertheless, some sequence constraints exist and reversions were observed. In this regard, the TN92 mutant appeared to be more stable than the TN14 mutant, an important attribute for use as a live vaccine. The vaccine strain persisted in one cat for as long as 1 year after inoculation, underscoring the risk of reversion to a virulent phenotype (Gundlach et al., 2000; Sawai et al., 2000
) or of pathogenicity for immunocompromised persons and infants or young children (reviewed by Desrosiers, 1994
; Mills et al., 2000
; Ruprecht, 1999
). Whilst poorly replicative, attenuated virus is likely to be less pathogenic in immunocompromised hosts, several studies have concluded that the degree of protection is correlated inversely with replicative capacity (Denesvre et al., 1995
; Johnson et al., 1999
; Wyand et al., 1996
). Live vaccines against lentivirus infections have largely been developed by alteration of accessory genes and subsequent diminution in replicative capacity. We now show that modification of a highly conserved domain in a virus structural protein may be used to manipulate immunogenicity and improve the safety and efficacy of live vaccines.
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ACKNOWLEDGEMENTS |
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Received 22 July 2004;
accepted 16 June 2005.
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