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Journal of Virology, May 2001, p. 4430-4434, Vol. 75, No. 9
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.9.4430-4434.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Rabies Virus-Based Vectors Expressing Human Immunodeficiency
Virus Type 1 (HIV-1) Envelope Protein Induce a Strong,
Cross-Reactive Cytotoxic T-Lymphocyte Response against Envelope
Proteins from Different HIV-1 Isolates
James P.
McGettigan,1,2
Heather D.
Foley,1,2
Igor
M.
Belyakov,3
Jay A.
Berzofsky,3
Roger J.
Pomerantz,1,4,5 and
Matthias J.
Schnell1,4,*
The Dorrance H. Hamilton Laboratories, Center
for Human Virology,1 and Departments of
Biochemistry and Molecular Pharmacology,4
Microbiology and Immunology,2 and
Medicine,5 Jefferson Medical
College, Thomas Jefferson University, Philadelphia, Pennsylvania
19107, and Molecular Immunogenetics and Vaccine Research
Section, Metabolism Branch, National Cancer Institute, Bethesda,
Maryland 208923
Received 22 November 2000/Accepted 26 January 2001
 |
ABSTRACT |
Novel viral vectors that are able to induce both strong and
long-lasting immune responses may be required as effective vaccines for
human immunodeficiency virus type 1 (HIV-1) infection. Our previous
experiments with a replication-competent vaccine strain-based rabies
virus (RV) expressing HIV-1 envelope protein from a laboratory-adapted HIV-1 strain (NL4-3) and a primary HIV-1 isolate (89.6) showed that
RV-based vectors are excellent for B-cell priming. Here we report that
cytotoxic T-lymphocyte (CTL) responses against HIV-1 gp160 are induced
by recombinant RVs. Our results indicated that a single inoculation of
mice with an RV expressing HIV-1 gp160 induced a solid and long-lasting
memory CTL response specific for HIV-1 envelope protein. Moreover, CTLs
from immunized mice were not restricted to the homologous HIV-1
envelope protein and were able to cross-kill target cells expressing
HIV-1 gp160 from heterologous HIV-1 strains. These studies further
suggest promise for RV-based vectors to elicit a persistent immune
response against HIV-1 and their potential utility as efficacious
anti-HIV-1 vaccines.
| |
TEXT |
New antiretroviral strategies
against human immunodeficiency virus (HIV) type 1 (HIV-1) have resulted
in a dramatic decrease in mortality among infected humans in developed
countries, but the development of a successful vaccine to prevent
infection is still the major goal to halt the HIV-1 pandemic. A human
being is infected with HIV-1 every 10 s on average, and in heavily
affected countries in Africa, such as Zambia and Uganda, nearly 40% of young adults are HIV-1 seropositive.
Currently, a variety of HIV vaccine strategies are being investigated,
including recombinant proteins (16, 33, 37), peptides
(6, 8, 30), naked DNA (3, 5, 10, 25, 32, 34,
38), replication-competent and non-replication-competent (replicon) live viral vectors (7, 13, 19, 27-29, 36), and
prime-boost combinations (for a review, see reference 4). A large number of these vaccine strategies have been tested in the
simian immunodeficiency virus (SIV) macaque model system, but to date
no potent protective immunity has been obtained, although some
amelioration of disease course has been seen (5, 13, 29).
So far, the only effective method for protecting macaques from SIV
infection is the use of live attenuated SIV. Studies showed that a
genetically modified, nef deletion SIV strain that does not
cause disease in rhesus monkeys induced high anti-SIV titers of
antibodies and cytotoxic T-lymphocyte (CTL) activity (12,
22). Subsequent challenge of the immunized animals with infectious doses of a pathogenic SIV strain yielded protection from
infection (12). A major drawback for the use of attenuated lentivirus vaccine approaches is the finding that even SIV with a
nef deletion can give rise to an AIDS-like disease in both
neonatal and adult macaques (1, 2, 14). Additional
concerns regarding the use of attenuated lentiviruses arise from the
recent finding that in some instances, recombination of live attenuated
SIV with challenge virus results in an even more virulent strain
(18). Nevertheless, study results have indicated that live
viral vectors may be excellent vaccine candidates for an HIV-1 vaccine.
We have recently developed a new potential HIV-1 vaccine based on an
attenuated replication-competent rabies virus (RV) expressing HIV-1
gp160 from both a laboratory-adapted strain (NL4-3) and a primary
HIV-1 isolate (89.6) (36). The HIV-1 envelope protein was
stably and functionally expressed and induced a strong humoral response
directed against the HIV-1 envelope protein after a single boost with
recombinant gp120 in mice. Moreover, high neutralization titers against
HIV-1 could be detected in the mouse sera.
The immune response(s) required to protect against HIV-1 infection is
currently unknown, but a protective immune response against HIV-1 might
require both major arms of the immune system. Recent reports on vaccine
approaches using recombinant HIV-1 envelope protein suggested that an
exclusively humoral response is not sufficient to protect against HIV-1
infection, but the passive transfer of three monoclonal antibodies
directed against HIV-1 envelope protein resulted in protection of
macaques against subsequent challenge with a pathogenic HIV-1/SIV
chimeric virus (26). Other studies indicated that a
cell-mediated response plays an important role in controlling HIV-1
infection (9, 17). Exposed but uninfected individuals
often have HIV-1-specific CTLs but no detectable antibodies against
HIV-1 (31, 35).
Little information is available regarding the induction of CTL
responses against foreign proteins expressed by rhabdovirus-based vectors. In this study, we analyze the potency of recombinant RVs
expressing HIV-1 envelope protein to induce HIV-1-specific CTLs.
Induction of long-lasting HIV-1 gp160-specific CTLs.
Our
previous experiments with a recombinant RV expressing HIV-1 envelope
protein from a laboratory-adapted HIV-1 strain (NL4-3) and a primary
HIV-1 isolate (89.6) showed that RV-based vectors are excellent for
B-cell priming (36). In the present study, we analyze the
memory CTL response against HIV-1 envelope protein expressed by
attenuated RV-based vectors. As noted, increasing evidence suggests
that the induction of a vigorous, long-lasting CTL response will be an
important feature for a successful HIV-1 vaccine.
To analyze the potency of RV-based vectors to induce a cytotoxic
response against HIV-1, we immunized six mice with 2 × 107 focus-forming units (FFU) of the previously
described (36) recombinant RV expressing
HIV-1NL4-3 envelope protein (SBN-NL4-3). Three
mice were sacrificed 105 or 135 days after infection, and the spleens
were removed. One-third of the splenocyte culture was infected at a
multiplicity of infection (MOI) of 1 with a recombinant vaccinia virus
expressing HIV-1NL4-3 gp160 for 16 h,
deactivated using psoralen (Sigma) and UV treatment, and added back to
the culture as presenter cells. Stimulated effector cells were
analyzed 7 days after activation for their ability to kill P815 target
cells infected with wild-type vaccinia virus, a recombinant vaccinia
virus expressing HIV-1NL4-3 gp160, or a
recombinant vaccinia virus expressing HIV-1 Gag.
As shown in Fig.
1, a strong cytotoxic
response was detected only against P815 target cells infected with the
recombinant
vaccinia virus expressing HIV-1 envelope protein. Only a
low percentage
of lysis was observed for P815 cells infected with the
other two
vaccinia viruses. Of note, these responses were achieved
after
a single inoculation with a recombinant RV expressing HIV-1
envelope
protein, indicating that RV-based vectors are able to induce
long-lasting
CTLs after a single vaccination.
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FIG. 1.
CTLs from HIV-1 gp160-immunized mice induce
long-lasting HIV-1 gp160-specific CTLs. Groups of three 6- to
8-week-old female BALB/c mice (Harlan Sprague-Dawley) were
inoculated i.p. with 2 × 107 FFU of recombinant RV
expressing HIV-1NL4-3 envelope protein. At 105 (A) to 135 (B) days after the single inoculation, spleens from three mice were
aseptically removed and combined, and single-cell suspensions were
prepared. Red blood cells were lysed with ACK lysing buffer
(BioWhittaker) and washed twice in RPMI-10 medium containing 10% fetal
bovine serum. Splenocytes were divided into effector and stimulator
cells. Stimulator cells were prepared by infection with vaccinia virus
expressing the envelope protein from HIV-1NL4-3 (vCB41)
( ) at an MOI of 1 for 2 h. Cells were washed once to remove
excess virus and incubated for 16 h. After incubation, the
vaccinia virus was inactivated using psoralen at a final concentration
of 5 µg/ml for 10 min, treated with long-wave UV for 4 min, and
washed twice. Stimulator cells were added back to the effector cell
population at a ratio of 3:1, and 10% T-STIM (Collaborative Biomedical
Products) was added as a source of interleukin-2. The cytolytic
activity of cultured CTLs was measured by a 4-h assay with
51Cr-labeled P815 target cells 7 days after in vitro
stimulation. Target cells were prepared by infection with vaccinia
virus expressing HIV-1NL4-3 gp160 for 1 h at an MOI
of 10. Cells were washed to remove excess virus and incubated for
16 h. To measure background, target cells were infected with
vaccinia virus expressing HIV-1 Gag (vP1287) ( ) or wild-type
vaccinia virus (vP1170) ( ). Target cells were washed once, labeled
with 100 µCi of 51Cr for 1 h, washed twice, and
added to effector cells at various E/T ratios for 4 h. The percent
specific 51Cr release was calculated as 100 × [(experimental release  spontaneous release)/(maximum
release spontaneous release)]. Maximum release was determined
from supernatants of cells that were lysed by the addition of 5%
Triton X-100. Spontaneous release was determined from target cells
incubated without added effector cells.
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CTLs from HIV-1 gp160-immunized mice cross-kill target cells
expressing heterologous HIV-1 envelope proteins.
There is a
significant difference in HIV-1 envelope amino acid sequences, but
cross-protection between divergent viruses will be a likely requirement
for a protective HIV-1 vaccine. To analyze the potency of our vaccine
candidate to induce cross-reactive CTLs against gp160 from different
HIV-1 strains, we screened splenocytes from mice immunized with a
recombinant RV expressing HIV-1 gp160 against P815 target cells
expressing homologous and heterologous HIV-1 envelope proteins. This
approach seemed to be most promising because the sequences of the HIV-1
envelope proteins used are quite different (Table
1) and this method does not require
knowledge of a certain epitope that is conserved among different HIV-1
envelope proteins. For HIV-1 gp160, no
H-2d-restricted CTL epitopes are known for
primary isolates (HIV Molecular Immunology Database, Los Alamos
National Laboratory, Theoretical Biology and Biophysics, Los Alamos,
N.Mex.).
Two groups of six mice were immunized intraperitoneally (i.p.) with
2 × 10
7 FFU of recombinant RV
expressing HIV-1 gp160 from a laboratory-adapted,
CXCR4-tropic
strain (NL4-3) or a dualtropic (CXCR4 and CCR5) isolate
(89.6).
Three and five weeks after immunization, three mice from
each group
were sacrificed, the spleens were removed, and the
pooled splenocytes
were stimulated with a recombinant vaccinia
virus expressing the
homologous HIV-1 envelope protein (NL4-3
or 89.6). Seven days after
stimulation, effector cells were analyzed
for their ability to lyse
P815 cells infected with recombinant
vaccinia viruses expressing HIV-1
envelope proteins from the laboratory-adapted,
CXCR4-tropic HIV-1
strain (NL4-3), the dualtropic strain (89.6),
and two primary,
CCR5-tropic HIV-1 strains (Ba-L and JR-FL).
The results from two different, independent experiments are shown in
Fig.
2A for mice immunized with an RV
expressing HIV-1
NL4-3 Env and in Fig.
2B for
mice immunized with an RV expressing HIV-1
89.6 Env. As expected, strong, specific lysis of P815 cells expressing
the
homologous antigen was observed for both groups. More striking,
the
effector cells were able to cross-kill P815 target cells expressing
heterologous HIV-1 envelope proteins. Activated splenocytes from
SBN-NL4-3-immunized mice achieved specific lysis of P815 cells
expressing gp160 from JR-FL or 89.6 in the 40% range at an
effector/target
(E/T) ratio of 50:1 and were also able to cross-kill
target cells
expressing HIV-1
Ba-L gp160.
Cross-killing was also observed with
effector cells from
SBN-89.6-primed mice. P815 target cells expressing
heterologous HIV-1
envelope protein were lysed in the same range
as that observed for
activated splenocytes from mice immunized
with SBN-NL4-3, except that
only about 20% of P815 cells expressing
HIV-1
NL4-3 were lysed. These data
indicate that CTLs against
HIV-1 gp160 induced by RV-based vectors may
be directed against
different epitopes within the HIV-1 envelope
protein.
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FIG. 2.
CTLs from HIV-1 gp160-immunized mice cross-kill target
cells expressing heterologous HIV-1 envelope proteins. Groups of six 6- to 8-week-old female BALB/c mice were inoculated i.p. with 2 × 107 FFU of recombinant RV expressing HIV-1 envelope protein
from strain NL4-3 (A) or 89.6 (B). At 3 and 4 weeks after the single
inoculation, spleens were aseptically removed, and splenocytes were
stimulated in vitro with vaccinia virus expressing the homologous HIV-1
envelope protein as described in the legend to Fig. 1. Target cells
were prepared by infection with vaccinia virus expressing HIV-1
envelope proteins from strain NL4-3 (vCB41) (), 89.6 (vBD3) ( ),
JR-FL (vCB28) ( ), or Ba-L (vCB43) ( ). To measure background,
target cells were infected with vaccinia virus expressing HIV-1 Gag
(vP1287) () or wild-type vaccinia virus (vP1170) (). Chromium
release assays were completed as described in the legend to Fig. 1. The
results shown are from two different, independent experiments. Error
bars show standard deviations.
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|
HIV-1-specific CTL activity is mediated by CD8+ T
cells.
The phenotype of the T-cell subpopulation mediating
cytolytic activity was assessed by selective depletion. Three mice were immunized with 2 × 107 FFU of a recombinant
RV expressing HIV-1NL4-3 envelope protein, and
the spleens were removed 18 weeks later. Splenocytes were restimulated
with a recombinant vaccinia virus expressing the homologous HIV-1
envelope protein for 7 days. Immunomagnetic bead cell separation was
completed to both deplete and positively isolate
CD8+ T cells from the activated splenocyte
culture. Chromium release assays were completed using cultures depleted
of CD8+ T cells (CD8
),
cultures of isolated CD8+ cells
(CD8+), or unprocessed cultures
(CD8+ CD8). P815 target
cells were infected with a vaccinia virus expressing HIV-1NL4-3 gp160 or HIV-1 Gag.
As shown in Fig.
3, the
CD8
+ T-cell-depleted cultures showed no activity,
while the CD8
+ T-cell-enriched and unprocessed
cultures showed high specific
lysis at E/T ratios of 25:1 and
12.5:1. Indeed, the CD8
+ T-cell-enriched
population was also enriched in lytic units,
as the CTL activity was
still on a plateau at 12.5:1, in contrast
to the results for the
unselected population. These data indicate
that cytolytic activity is
mediated by the CD8
+ T-cell subpopulation.
Furthermore, these results suggest that
in addition to antibodies,
recombinant RV-based vectors also generate
long-lived anti-HIV-1
CD8
+ T-cell responses.
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FIG. 3.
Cytolytic activity is mediated by CD8+ T
cells. Groups of three 6- to 8-week-old female BALB/c
mice were inoculated i.p. with 2 × 107 FFU of
recombinant RV expressing HIV-1 envelope protein from the NL4-3
strain. At 18 weeks after the single inoculation, spleens were
aseptically removed, and splenocytes were stimulated in vitro with
vaccinia virus expressing HIV-1NL4-3 envelope protein as
described in the legend to Fig. 1. At 7 days after in vitro
stimulation, CD8+ T cells were depleted from the cell
culture (CD8) or enriched (CD8+) using
Dynabeads mouse CD8 (Lyt2) as described by the manufacturer.
Chromium release assays were completed as described in the legend to
Fig. 1 with cultures depleted of (CD8) or enriched for
(CD8+) CD8 T cells or (CD8+ CD8)
unprocessed cultures. Target cells were prepared by infection with
vaccinia virus expressing HIV-1 envelope protein from NL4-3 (vCB41).
To measure background, target cells were infected with vaccinia virus
expressing HIV-1 Gag (vP1287). Background levels were equal to or below
6% specific lysis. E/T ratios were 25:1 (gray bars) and 12.5:1 (black
bars).
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Summary.
We previously demonstrated that RV-based vectors
expressing HIV-1 envelope proteins are able to induce a humoral
response against HIV-1 gp160 after a single immunization followed by a booster injection with recombinant HIV-1 gp120 (36).
Expanding evidence suggests that CTL responses play a major role in the immune response against HIV-1 (9). The development of an
effective prophylactic HIV-1 vaccine therefore probably requires the
selection of an HIV-1 antigen(s) capable of inducing long-lasting and
broadly reactive CTL responses. The results presented here indicate
that RV-based vectors are excellent vectors for inducing such
responses. In contrast to the observed humoral response, a single
inoculation of mice with a recombinant RV expressing HIV-1 envelope
protein resulted in a vigorous CTL response against HIV-1 Env. In
addition, this response was stable for at least 135 days after
immunization. One explanation for the strong response may be that RV
grows in various cell lines without killing the cells, a characteristic which probably results in longer-lasting expression of HIV-1 genes than
that seen with a cytopathogenic viral vector. In addition, the
expression of the RV nucleoprotein, which was previously shown to be an
exogenous superantigen (23, 24), might help to enhance a
general immune response against the HIV-1 envelope protein after a
single immunization.
Our recombinant RVs were able to induce cross-reactive CTLs against a
variety of different HIV-1 envelope proteins. Previous
studies showed
that single amino acid exchanges can abrogate CTL
cross-reactivity, but
other examinations indicated that single
or even double amino acid
substitutions frequently do not abrogate
cross-killing (
11,
20,
21). Therefore, the question remains
as to whether CTLs induced
by recombinant RVs are directed against
different epitopes. However,
our results are encouraging because
several studies have indicated that
CTLs from HIV-1-infected individuals
show cross-reactivity even with
different clades of HIV-1; thus,
broad cross-reactivity is an important
requirement for an HIV-1
vaccine (
11,
35). To our
knowledge, only one study has shown
cross-clade CTL reactivities
induced with a canarypox virus-based
HIV-1 vaccine in uninfected
volunteers (
15). We are currently
analyzing whether CTLs
induced against HIV-1 gp160 by recombinant
RVs are also cross-reactive
against HIV-1 envelope proteins from
clades other than
B.
In summary, we have shown that a single vaccination with a recombinant
RV expressing HIV-1 envelope protein elicits a strong,
long-lasting CTL
response against envelope proteins of different
HIV-1 strains. These
results further emphasize the use of RV as
a potential HIV-1 vaccine.
In contrast to the situation for most
other viral vectors, only
negligible seropositivity for RV exists
in the human population, and
immunization with an RV-based vector
against HIV-1 would not interfere
with immunity against the vector
itself. Because oral immunization
against RV with an RV vaccine
strain was successful and apathogenic in
chimpanzees (World Health
Organization, unpublished document W. H. O./Rab.Res./93.42), an
RV-based vector may also be promising in
inducing mucosal immunity
against HIV-1. Further exploration of this
vaccine strategy in
macaques will indicate the usefulness of such
vectors in inducing
protective immunity against HIV-1.
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ACKNOWLEDGMENTS |
Recombinant vaccinia viruses expressing HIV-1 envelope protein were
obtained through the AIDS Research and Reference Reagent Program
(ARRRP), Division of AIDS, NIAID, NIH. We thank Rita Victor and Brenda
Gordon for excellent secretarial assistance.
This study was supported by NIH grant AI44340, AmfAR grant
02697-28-RGV, and internal Thomas Jefferson University funds to M.J.S.
and the Center for Human Virology.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: 1020 Locust
Street, Suite 335, Philadelphia, PA 19107-6799. Phone: (215) 503-1260. Fax: (215) 923-1956. E-mail:
matthias.schnell{at}mail.tju.edu.
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Journal of Virology, May 2001, p. 4430-4434, Vol. 75, No. 9
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.9.4430-4434.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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