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Journal of Virology, May 2001, p. 4424-4429, Vol. 75, No. 9
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.9.4424-4429.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
AIDS Vaccination Studies Using an Ex Vivo Feline
Immunodeficiency Virus Model: Reevaluation of Neutralizing Antibody
Levels Elicited by a Protective and a Nonprotective Vaccine after
Removal of Antisubstrate Cell Antibodies
Simone
Giannecchini,
Daniela
Del Mauro,
Donatella
Matteucci, and
Mauro
Bendinelli*
Department of Biomedicine and Retrovirus
Center, University of Pisa, Pisa, Italy
Received 8 December 2000/Accepted 30 January 2001
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ABSTRACT |
In the feline immunodeficiency virus system, immunization with a
fixed-infected-cell vaccine conferred protection against virulent
homologous challenge but the immune effectors involved remained
elusive. In particular, few or no neutralizing antibodies were detected
in sera from vaccinated cats. Here we show that, when preadsorbed with
selected feline cells, the same sera revealed clearly evident
virus-neutralizing activity. Because high titers of neutralizing
antibody in cell-adsorbed sera from 23 cats immunized with
fixed-infected-cell or whole-inactivated-virus vaccines correlated with
protection, it is likely that they were more important for protection
than formerly realized. In vitro, the fixed-cell vaccine efficiently
removed neutralizing antibody from immune sera while the
whole-inactivated-virus vaccine was much less effective.
| |
TEXT |
Studies with animal models have
shown that certain experimental vaccines can prevent lentiviral
infections or retard progression to disease, but the immune effectors
responsible for these protective effects have remained elusive
(reviewed in references 9, 10, 15, 17, and 25). In the
feline immunodeficiency virus (FIV) system (26, 33),
substantial levels of protection have been achieved with several
immunogens, including fixed-infected-cell (FC) and
whole-inactivated-virus (WIV) vaccines (3, 6, 11, 12, 18, 19, 21,
34, 35), two types of immunogens that have provided some
satisfactory results also against simian immunodeficiency virus
(5, 14). Thus, FIV is a practical model for investigating correlates of vaccine-induced immunity to lentiviruses.
In previous studies, it was found that an FC vaccine, consisting of
feline lymphoid cells acutely infected with the clade B primary isolate
FIV-M2, fixed with paraformaldehyde (1.25%, 37°C for 24 h) at
the peak of viral antigen surface expression, effectively protected
cats against systemic challenge with fully virulent, ex vivo-derived
cell-free and cell-associated homologous virus (18, 19).
However, thorough investigation of the elicited immune response failed
to identify correlates that might explain the protection. Due to their
importance in prophylactic immunization in general (27),
virus-neutralizing antibodies (NA) were a special focus of attention
but were detected in only a few sera from vaccinated animals, without
correlation to protected or unprotected status (22). Here,
we show that failure to detect NA in such sera was due to the presence
of vaccine-induced antibodies directed to cellular antigens and
removable by adsorption with selected feline cells. In light of this
finding, we have reinvestigated the levels of NA in cell-adsorbed sera
of cats immunized with the above-mentioned FC vaccine (hereafter
referred to as FC vaccine sera) and with a nonprotective WIV vaccine.
FC vaccine sera contain anticell antibodies that prevent NA
detection in vitro.
Because the anti-FIV FC vaccine was known to
elicit moderate levels of antibodies to substrate cell antigens
(19), before definitely excluding NA as possible
contributors to its protective action, we checked whether failure of
vaccinated-cat sera to inhibit FIV infectivity in vitro might be due to
the presence of cell-reactive factors that interfered with the outcome
of in vitro neutralization assays. To this end, we adsorbed with
selected cell types the sera of vaccinated specific-pathogen-free (SPF)
cats that had repeatedly been found to be NA negative in previous
assays (22) and retested their ability to inhibit FIV
infectivity in vitro. The cells used for adsorption were MBM cells
(i.e., the same feline lymphoid cells as used for vaccine preparation),
freshly harvested feline peripheral blood mononuclear cells (PBMC),
primary lymphoblasts obtained from PBMC stimulated with concanavalin A
for 3 (PLB-d3) or 12 (PLB-d12) days, Crandell feline kidney (CrFK)
cells, and human oral epidermoid carcinoma KB cells. For adsorption,
0.8 ml of a 1:8 dilution of heat-inactivated sera was incubated with 106 viable packed cells at 4°C for 1 h with
occasional shaking, spun down, incubated with the same number of fresh
cells at 37°C for 1 h, and then centrifuge clarified. Adsorbed
and untreated sera, diluted 1:16, 1:64, 1:256, and 1:1,024 (dilutions
before the addition of virus and cells), were tested in parallel for NA
against 10 50% tissue culture infectious doses of a stock of
low-passage FIV-M2 prepared in MBM cells. The NA assay was routinely
carried out using indicator MBM cells. The only deviation from the
previously described procedure (4) was that the
virus-serum mixtures were removed from the indicator cultures and
replaced with fresh complete medium 3 h after inoculation. This
modification was suggested by findings showing that, by this time,
FIV-M2-exposed MBM cells already contain substantial copy numbers of
proviral DNA (results not shown).
Table 1 shows the NA titers exhibited by
cell-adsorbed and untreated sera of FC-vaccinated cats. Similar to
their untreated counterparts, FC vaccine sera preadsorbed with PBMC or
PLB-d3 or KB cells had minimal or no neutralization activity. In
contrast, following adsorption with MBM, PLB-d12, or CrFK cells, the
same sera effectively inhibited FIV replication. It is also important to note that, at low dilutions, the untreated FC vaccine sera caused a
moderate but clearly evident enhancement of FIV replication and that
this effect was lost after adsorption with MBM, PLB-d3, or PLB-d12
cells but not with freshly harvested PBMC (Fig.
1). When probed by flow cytometry with
vaccine sera strongly reactive with MBM cells PLB-d3, PLB-d12, and CrFK
cells were found to share increasing amounts of surface antigen(s) with
MBM cells, while PBMC tested totally negative (data not shown). On the
other hand, adsorption with MBM cells had no effect on NA-positive and
NA-negative control sera obtained from infected and naive cats (Table
1). We also examined whether the FIV-inhibitory effect of cell-adsorbed FC vaccine sera was affected by immunoglobulin G (IgG) depletion. The
sera, adsorbed with MBM cells and diluted 1:64, were incubated at room
temperature for 2 h in microwells that had been coated overnight
with 10 µg of goat anti-cat IgG (whole molecule) serum (Sigma, St.
Louis, Mo.) and postcoated with skim milk and, as a control, in
microwells coated with skim milk alone. Effective IgG capture was
demonstrated by probing the wells with biotinylated mouse anti-cat IgG
serum (Sigma) followed by an antibiotin-peroxidated conjugate and
reading the optical density at 450 nm. As shown by Fig.
2, the FIV-inhibitory effect of adsorbed
FC vaccine sera was abolished by IgG depletion, thus demonstrating that
it was the result of true virus antibody-mediated neutralization and not of unidentified virus-blocking factors released by the cells used
for adsorbing the sera. Further experiments demonstrated that,
following MBM cell adsorption, FC vaccine sera acquired the ability to
neutralize FIV infectivity also for mitogen-stimulated PBMC.
Furthermore, the adsorbed sera failed to neutralize two heterologous
clade B viruses grown in MBM cells exactly as the homologous virus
(results not shown), thus showing the virus isolate specificity typical
of FIV-infected cat sera (1, 4).
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TABLE 1.
Effects of preadsorbing with selected cell types on the
FIV-neutralizing activity of FC vaccine sera and control infected and
naive cat sera
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FIG. 1.
Effects of adsorption with selected cell types on the
FIV neutralization curves produced by FC vaccine sera. The sera were
adsorbed with MBM cells (×|), PBMC ( ), or PLB-d3
( ) or PLB-d12 ( ) cells or manipulated in the same manner except
for omission of cells ( ). RT, reverse transcriptase.
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FIG. 2.
Effects of IgG depletion on the FIV-neutralizing
activity of MBM cell-adsorbed FC vaccine sera. Prior to neutralization,
the indicated sera were depleted of IgG by capture onto anti-cat IgG
(whole molecule) serum-coated microwells (broken lines) or manipulated
in the same manner except for omission of anti-IgG serum (continuous
lines). RT, reverse transcriptase.
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We also examined whether the addition of sera obtained from cats
immunized with uninfected paraformaldehyde-fixed MBM cells
affected the
NA titer of otherwise neutralizing sera. Pooled sera
from 3 cats
infected with FIV-M2 1 year earlier were mixed 1:1
with undiluted or
diluted pooled sera from 2 cats immunized with
a mock MBM cell-based FC
vaccine (hereafter referred to as mock-vaccine
sera) in incomplete
Freund's adjuvant (cats 743 and 3583 in reference
19)
and, as a control, with undiluted pooled sera from 10 normal
cats. The
mixtures were then titrated for NA. As shown by Fig.
3, the mock-vaccine serum reduced the NA
titers of infected cat
sera in a dose-dependent fashion whereas naive
cat serum did not.
Importantly, mock-vaccine sera failed to neutralize,
regardless
of whether they were MBM cell adsorbed. Sera from two cats
immunized
with fixed CrFK cells exerted a similar though slightly less
pronounced
effect, while sera from cats immunized with autologous
PLB-d3
cells did not (data not shown). Furthermore, the effect of
mock-vaccine
serum was abolished by MBM cell adsorption and IgG
depletion (Fig.
3).
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FIG. 3.
Effects on the FIV-neutralizing activities of serum from
FIV-infected cats of mixing with sera from cats immunized with a mock
vaccine consisting of fixed uninfected MBM cells. NA titers are
expressed as in Table 1. The experiment was repeated three times, with
comparable results.
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Collectively, the above findings demonstrated that the FC vaccine had
elicited virus-specific antibodies capable of neutralizing
the FIV
strain used for vaccine preparation and that previous
failure to
demonstrate such NA in in vitro neutralization tests
was due to the
presence in the sera of antibodies directed to
the surfaces of feline
cells and elicited by the cell substrate
used for vaccine preparation.
It is well known that, during budding
from the plasma membrane,
lentiviruses incorporate into their
envelopes relatively vast amounts
of a wide array of functional
host cell materials (reviewed in
reference
31). Thus, it is
possible that anticell
antibodies compete physically with NA on
the virion surface or
counteract their action by some other mechanism.
The presence of
certain host cell-derived molecules in the viral
envelope has been seen
to increase the resistance of human immunodeficiency
virus type 1 (HIV-1) to antibody-mediated neutralization (
31),
and it
is plausible that antibodies reactive with such molecules
might magnify
this effect. Alternatively, anticell antibodies
might cross-link
virions and cells and hence augment FIV infectivity
for neutralization
indicator cells. Previous studies have shown
that in the case of HIV-1,
some ligands, such as oligomers of
the RANTES CC-chemokine, can
facilitate virus infection also indirectly,
namely by binding to cells
and increasing their permissiveness
(
32). However,
preincubation of MBM cells with the mock-vaccine
sera that in the
experiment described above had effectively reduced
the neutralizing
activity of FIV-infected cat sera had no effect
on FIV replication
(results not shown), thus excluding the latter
type of mechanism.
Future studies are warranted to investigate
in depth how anticell
antibodies can counteract NA in vitro as
well as the precise nature of
the cellular antigen(s) to which
they are directed. The spectrum of
cells which proved effective
at removing the relevant antibodies
suggests that such an antigen(s)
is especially abundant or present
solely on actively cycling
cells.
Levels of NA in cell-adsorbed day-of-challenge sera from protected
and unprotected vaccinated cats.
We systematically adsorbed with
MBM cells and compared for NA content three groups of day-of-challenge
FC-vaccinated SPF cat sera which, as discussed in a previous report
(22), were considered particularly informative due to
differences in timing and outcome of challenge, which was performed
with homologous ex vivo cell-free or cell-associated FIV. The results
with untreated sera were in line with our previous findings
(22) in that only one group 1 serum neutralized FIV
(titer, 256). Following cell adsorption, all group 1 and 2 sera
exhibited NA at a titer of 512 (10 cats) or 256 (2 cats), while only
half of group 3 sera neutralized FIV and, with one exception, their
titers were uniformly lower (Table 2).
Thus, these results demonstrated that NA were at higher titers in
protected than in unprotected vaccinees, supporting the concept that NA
had played a role in protection, possibly in concert with other immune
effectors (13, 22). It is noteworthy that a 50% end point
neutralization titer of 500 has been proposed as a desirable target for
HIV-1 vaccines because it is considered adequate for conferring solid
protection (23).
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TABLE 2.
Titers of FIV-neutralizing antibodies in MBM
cell-adsorbed day-of-challenge sera from vaccinated cats that had
proven protected or unprotected against homologous challenge
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Since under certain immunization conditions host-derived proteins bound
to lentiviral virions may trigger the formation of
cell-reactive
antibodies (
2,
16,
30), it was also of interest
to
determine whether elicitation of anticell antibodies capable
of
counteracting the in vitro activity of NA extended to a cell-free
WIV
vaccine. We therefore adsorbed with MBM cells and tested for
NA
day-of-challenge sera (group 4 in Table
2) from SPF cats that
had been
immunized with paraformaldehyde-inactivated (0.5%, at
37°C for
24 h), gradient-purified FIV-M2 produced in MBM cells.
These cats
had not resisted a mild systemic challenge with homologous
ex vivo
virus (
20). When tested untreated, the sera failed to
neutralize as in previously performed tests (
20), but
following
cell adsorption, three of five sera proved clearly
neutralizing,
albeit at lower titers than those observed with group 1 and 2
FC vaccine sera. These findings hence showed that WIV vaccines
can also elicit anticell antibodies capable of affecting the results
of
in vitro NA assays. They further indicated that the WIV vaccine
had
elicited a poorer NA response than the FC vaccine, thus correlating
with failure to
protect.
Depletion of NA in vitro by different immunogens.
In an
attempt to understand why the WIV vaccine had triggered less NA
formation than the FC vaccine, we evaluated the two immunogens for the
ability to deplete the FIV-neutralizing activity of immune sera in
vitro. For comparison, a preparation of viable FIV-M2 produced and
gradient purified as for the WIV vaccine preparation (19)
but not paraformaldehyde inactivated and FIV-M2 glycoproteins purified
with Galanthus nivalis lectin as described previously (8) were also examined in this regard. FIV-immune sera,
diluted 1:64, were incubated in microwells that contained 2 × 105 FC vaccine cells or had been coated overnight with 1 µg of the other antigens being tested. Incubation was carried out
first at 4°C for 1 h and then, on fresh microwells, at 37°C
for 1 h. The sera thus treated were high-speed centrifuged, heated
at 56°C for 1 h to eliminate any acquired viral infectivity, and
finally tested for NA. As shown in Table
3, preincubation of sera with the FC
vaccine led to substantial reductions of the NA titers of test immune
sera. Preincubation with viable FIV-M2 also removed NA, albeit slightly
less efficiently. In contrast, preincubation with the WIV vaccine had
only marginal effects on the NA titers of immune sera, indicating that
paraformaldehyde inactivation had impaired the functionality of
neutralization-relevant epitopes present on virions, possibly as a
consequence of conformational changes (7, 24, 29). As
expected, purified FIV glycoproteins also failed to adsorb NA.
Conclusions.
This study has shown that the sera of cats
immunized with anti-FIV FC and WIV vaccines can contain antibodies
directed to the substrate cells used for vaccine preparation and
capable of preventing the detection of virus-specific neutralizing
activity in in vitro assays. Interestingly, following removal of such
masking antibodies, day-of-challenge sera of FC-vaccinated cats that
had been found to be protected against fully virulent homologous FIV exhibited higher NA titers than the sera of unprotected FC- or WIV-vaccinated animals. Clearly, this raises the possibility that NA
were more important effectors of FC vaccine-induced protection than
formerly realized (22). A role for NA in vaccine-induced anti-FIV immunity has always been deemed likely, although attempts to
unequivocally correlate them with protection have generated inconsistent findings (13, 22). Also of interest is that
in vitro, the WIV vaccine removed far fewer NA from immune sera than the FC vaccine or viable cell-free virus, indicating that
paraformaldehyde treatment is more harmful for the neutralization
epitopes present on cell-free virions than for the ones expressed on
virus-infected cells. Since this meager immune reactivity in vitro
corresponded to a poor NA-inducing capacity of the WIV vaccine in vivo,
the ability to adsorb NA in vitro should be further evaluated as a possible parameter for screening candidate anti-FIV immunogens prior to
their use in animals. It is hoped that this and other evidence raised
in the FIV model will be of value also in the design and evaluation of
other antilentiviral vaccines.
| |
ACKNOWLEDGMENTS |
This work was supported by grants from the Ministero della
Sanità
Istituto Superiore di Sanità, "Programma per
l'AIDS," and from the Ministero della Università e Ricerca Tecnologica.
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FOOTNOTES |
*
Corresponding author. Mailing address: Dipartimento di
Biomedicina, Università di Pisa, Via San Zeno 37, I-56127 Pisa,
Italy. Phone: 39-050-553562. Fax: 39-050-559455. E-mail:
bendinelli{at}biomed.unipi.it.
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Journal of Virology, May 2001, p. 4424-4429, Vol. 75, No. 9
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.9.4424-4429.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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