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Journal of Virology, September 2000, p. 8762-8766, Vol. 74, No. 18
Divisions of
Immunology,1
Pathology,2 and Primate
Medicine,4 New England Regional Primate Research
Center, Harvard Medical School, Southborough, Massachusetts 01772;
Emory Vaccine Center at Yerkes, Emory University School of
Medicine, Atlanta, Georgia 303223;
Wisconsin Regional Primate Research Center, University of
Wisconsin, Madison, Wisconsin 537155; and
Infectious Disease Unit and Partners AIDS Research Center,
Massachusetts General Hospital, Harvard Medical School,
Charlestown, Massachusetts 021156
Received 18 February 2000/Accepted 5 June 2000
Induction of virus-specific T-cell responses in mucosal as well as
systemic compartments of the immune system is likely to be a critical
feature of an effective AIDS vaccine. We investigated whether
virus-specific CD8+ lymphocytes induced in rhesus macaques
by immunization with attenuated simian immunodeficiency virus (SIV), an
approach that is highly effective in eliciting protection against
mucosal challenge, express the mucosa-homing receptor Transmission of human
immunodeficiency virus (HIV) infection occurs predominantly across
genital or rectal mucosal surfaces. Following viral dissemination, the
large pool of activated CD4+ T cells that reside in
gut-associated lymphoid tissue (GALT) serves as a predominant site of
HIV or simian immunodeficiency virus (SIV) replication (25, 26,
28). Thus, the ability of virus-specific immune responses to
prevent or contain HIV or SIV replication in mucosal sites is likely to
play a critical role in the ability of the host to defend itself
against lentiviral infection.
The mucosal immune system is functionally and phenotypically distinct
from the peripheral immune system (3, 20). Induction of
immune responses by peripheral immunization at cutaneous or intramuscular sites results in antigen-specific lymphocytes that do not
efficiently traffic to mucosal sites (3, 20). Homing of
lymphocytes to cutaneous or mucosal sites is determined in part by
expression of cell surface adhesion molecules (5). The
intestinal homing receptor Despite evidence for the compartmentalization of peripheral and mucosal
immune systems, little information is available on the ability of
different AIDS vaccine strategies to induce cytotoxic T lymphocytes
(CTL) that are able to home to mucosal sites. HIV-1 and SIV-specific
CTL have been detected in genital and gastrointestinal mucosal tissues
following infection with pathogenic viruses (8, 19, 21, 22).
However, there has been little or no information on the ability of
candidate AIDS vaccines to induce cellular immune responses at
mucosal sites. In this study, we asked whether
CD8+ T cells induced in macaques by immunization with
attenuated SIV express the intestinal homing receptor In general, induction of memory lymphocytes expressing
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Copyright © 2000, American Society for Microbiology. All rights reserved.
Induction of Mucosal Homing Virus-Specific CD8+ T
Lymphocytes by Attenuated Simian Immunodeficiency Virus
ABSTRACT
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Abstract
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References
4
7 and
traffic to the intestinal mucosa. SIV-specific CD8+ T cells
expressing 47 were detected in peripheral blood and intestine of
macaques infected with attenuated SIV. In contrast, virus-specific T cells in blood of animals immunized cutaneously by
a combined DNA-modified vaccinia virus Ankara regimen did not express
47. These results demonstrate the selective induction of
SIV-specific CD8+ T lymphocytes expressing 47 by a
vaccine approach that replicates in mucosal tissue and suggest that
induction of virus-specific lymphocytes that are able to home to
mucosal sites may be an important characteristic of a successful AIDS vaccine.
TEXT
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Abstract
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References
47 plays a central role in directing migration of lymphocytes into intestinal mucosal tissue
(30). Lymphocytes expressing 47 bind to the mucosal
addressin MAdCAM-1, which is selectively expressed on capillary
endothelium in gastrointestinal immune inductive and effector sites
(4, 12).
47 and home
to gastrointestinal lymphoid tissue. Induction of
47+ virus-specific CD8+ T cells was also
investigated in monkeys that were immunized cutaneously with a combined
DNA-modified vaccinia virus Ankara strain vaccine expressing an
immunodominant SIV CTL epitope.
47
requires viral infection at gastrointestinal sites and is not observed
with infection at extraintestinal sites (24). However, because replication of attenuated SIV occurs preferentially in the pool
of activated CD4+ T lymphocytes found in GALT, even
following intravenous infection (28), we reasoned that
macaques intravenously infected with attenuated SIV would have
SIV-specific CD8+ T cells that express 47. To address
this hypothesis, we studied adult rhesus macaques infected
intravenously with either SIVmac239
nef, containing a
182-bp deletion in nef (17), or
SIVmac2933, which contains deletions in nef,
vpr, and upstream short sequences of the long terminal
repeat (31) 5 to 10 years after infection. Two of these
animals, 353.88 and 71.88, had been challenged intravenously with
pathogenic SIVmac239 or SIVmac251 3 to 7 years earlier; none of the monkeys exhibited evidence of infection with
pathogenic virus at the time of this study (10, 31).
SIV-specific CD8+ T cells were identified by multiparameter
flow cytometry using tetramers of the rhesus major histocompatibility
complex (MHC) class I molecule Mamu-A*01 complexed with the
immunodominant Gag peptide p11C,C
M (CTPYDINQM) (1,
13). Tetramers were prepared from purified monomers by the
gradual addition over 24 h of a allophycocyanin
(APC)-streptavidin (Molecular Probes) to a 4:1 final molar ratio. Four
monkeys were identified as expressing Mamu-A*01 using the PCR SSP as
previously described (18). Immunofluorescent staining was
performed on Ficoll-Hypaque-isolated peripheral blood mononuclear cells (PBMC) or whole blood using Mamu-A*01-peptide tetramers and anti-47 antibody (a gift from LeukoSite, Inc.) on a
FACSCalibur flow cytometer (Becton Dickinson). Four-color analysis of
CD3+ CD8+ gated lymphocytes revealed between
0.28 and 0.95% tetramer-binding cells in peripheral blood of live
attenuated SIV-immunized monkeys (Fig. 1A
and Table 1). Two monkeys infected
with wild-type SIV (SIVmac239) had 0.93 and 0.32%
tetramer-binding CD8+ T cells (Fig. 1B and Table 1).
Simultaneous analysis of tetramer binding and expression of 47
revealed that between 36 and 84% of SIV-specific CD8+ T
cells in animals vaccinated with live attenuated SIV expressed 47, a frequency generally similar to the level of expression on
all CD3+ CD8+ T cells. A comparable percentage
of tetramer binding cells in wild-type SIV-infected animals expressed
47. These findings support the conclusion that replication of
attenuated SIV in intestinal lymphoid tissue results in a
virus-specific CD8+ T cell response that is capable of
intestinal homing. These results are also consistent with a previous
report describing expression of 47 by circulating T cells
recognizing rotavirus, a pathogen for which replication is generally
restricted to the small intestine (24).
View larger version (41K):
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FIG. 1.
The mucosal homing receptor 47 is expressed on
SIV-specific CD8+ T cells in peripheral blood of attenuated
SIV-infected but not DNA-MVA-immunized macaques. PBMC from macaques
infected with attenuated SIV (A) or pathogenic SIVmac (B)
were analyzed by flow cytometry for tetramer binding and 47
expression after gating on CD3+ and CD8+
lymphocytes. The percentage of cells in each quadrant is indicated for
each plot. (C) PBMC from macaques immunized cutaneously with DNA and
MVA. PBMC were analyzed by flow cytometry for tetramer binding and
47 expression on CD3+ CD8+ lymphocytes 1 week after the last boost.
TABLE 1.
Expression of the mucosal homing receptor 47 on
SIV-specific CD8+ T cells in peripheral blood of
vaccinated monkeys
In order to examine whether induction of 47+
SIV-specific CD8+ T cells necessarily requires antigen
presentation in gastrointestinal tissue, we examined the phenotype of
SIV-specific CD8+ T cells induced by cutaneous
immunization with DNA and modified vaccinia virus Ankara (MVA).
Three Mamu-A*01-positive macaques were immunized with a
multiepitope gene using a DNA prime-MVA boost regimen as described
previously, which has been shown to induce p11C,CM-specific CTL
in peripheral blood of immunized macaques (2, 14). The DNA
vaccine was administered to the skin on five occasions using the Dermal
PowderJect XR "gene gun" (PowderJect Vaccines, Madison, Wis.),
followed by two boosts with MVA delivered intradermally. Cutaneous
immunization with MVA results in localized expression of viral
antigens, since MVA infects but does not replicate in mammalian cells
(27), and thus tetramer-positive CD8+ T cells
induced by immunization with DNA-MVA would be expected to be negative
for 47. We therefore examined blood from DNA-MVA-immunized monkeys for tetramer binding and 47 expression. In contrast to
CD8+ T cells from monkeys infected with attenuated SIV,
tetramer-binding cells induced by the DNA-MVA vaccine regimen 1 week
after a cutaneous MVA boost did not express 47 (Fig. 1C). Similar
results were observed at 2 and 3 weeks after MVA boosting (data not
shown). These results suggest that antigen-specific T cells induced by cutaneous immunization with vaccines that do not disseminate to GALT
are unlikely to express 47, a conclusion supported by the prior
observation that memory T cells induced by peripheral immunization with
an attenuated mumps vaccine did not express 47 (24). However, the DNA-MVA- and attenuated SIV-vaccinated animals may differ
in several respects, including the degree of T-cell activation and the
presence of T-cell help, and further studies with expanded numbers of
vaccinated animals will be necessary to document whether expression of
47 on antigen-specific T cells is necessarily induced only by
antigen presentation in GALT.
Having established that attenuated SIV immunization elicits
47+ SIV-Gag-specific CTL in peripheral blood, we
investigated whether cells with this phenotype were able to home to
gastrointestinal mucosal sites. Lymphocytes were isolated from
endoscope-guided pinch biopsies of duodenum and colon and excisional
biopsies of peripheral lymph node from four macaques immunized with
attenuated SIV, and the cells were analyzed for expression of 47
and tetramer binding. Cells were isolated from intestinal tissues using
a combination of mechanical and enzymatic dissociation procedures
described elsewhere (29). Lymphocyte populations isolated
using this procedure include a mixture of intraepithelial and lamina
propria lymphocytes. SIV-specific CD8+ T cells were
detected in peripheral lymph nodes and in both intestinal sites of all
four animals. Three of four monkeys exhibited increases of 2- to
20-fold in tetramer-binding cells in one or both intestinal sites
compared to levels in peripheral blood (Table
2 and Fig. 2). Higher percentages of
tetramer-binding cells were also found in peripheral lymph nodes
relative to levels in blood in two out of three animals. At least 50%
of tetramer-binding cells in duodenum, colon, and lymph node expressed
47, a similar proportion to that observed in peripheral blood. As
expected, the total CD3+ CD8+ lymphocyte
population in duodenum and colon were enriched for 47+ cells compared to these populations in peripheral
blood and lymph node (Table 2).
|
|
The ability of virus-specific T cells to home to mucosal sites of viral
replication plays a critical role in their ability to control viral
replication. Evidence for the importance of mucosal homing can be found
in pulmonary influenza virus infection, where the ability of adoptively
transferred CD8+ T cells to migrate to the site of
infection is critical for protection (6). This also appears
to be the case in intestinal rotavirus infection, where viral clearance
has been correlated with induction of virus-specific CD8+ T
cells expressing 47 (23). Similarly, subcutaneous
immunization of mice with an HIV peptide immunogen induced systemic but
not mucosal CTL and failed to protect mice against rectal challenge with a recombinant vaccinia virus expressing the HIV-1 envelope, whereas rectal immunization induced both mucosal and systemic CTL and
protection against mucosal challenge (3). It is probable that mucosal homing will prove to also be important for protection against HIV and SIV infection. While the DNA prime-MVA boost
vaccination regimen (14), as well as several other HIV
vaccine approaches (7, 11), are effective at inducing
virus-specific CD8+ T cells, no information is presently
available regarding the mucosal homing ability of cells induced by
these vaccines, and little is known about their protective effects. Our
recent results suggest that virus-specific CD8+ T cells
induced by the DNA-MVA vaccine may not be able to traffic to the
intestine, possibly rendering this approach less effective in inducing
protection against SIV or HIV infection. Consistent with this
hypothesis, an initial report examining the ability of a cutaneous
DNA-MVA vaccination regimen to protect against rectal SIV challenge
failed to observe protection in two of three animals studied, despite
the fact that levels of tetramer-binding cells at the time of challenge
ranged from 1 to 5% of CD8+ T cells in peripheral blood
(14), a level approximately two- to fivefold greater than we
observed in animals vaccinated with attenuated SIV. In contrast,
attenuated SIV immunization has previously been shown to protect
against rectal and vaginal SIV challenge (9, 16).
In summary, our results indicate that virus-specific CD8+ T
cells are induced by immunization with attenuated SIV express 47 and home to mucosal sites, whereas those induced by a DNA-MVA vaccine
lack expression of the intestinal homing receptor. Since induction of
virus-specific immune responses in mucosal sites is likely to be a
critical component of an effective AIDS vaccine, these findings may
have important implications for future vaccine design.
All animals were maintained in accordance with the Guide for the Care and Use of Laboratory Animals (15) and institutional animal use committee guidelines.
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ACKNOWLEDGMENTS |
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This work was supported by Public Health Service grants RR00168, AI43044, AI43045, and DK50550. R.P.J., A.A.L., and D.I.W. are Elizabeth Glaser Scientists and are supported by the Elizabeth Glaser Pediatric AIDS Foundation.
We thank Ron Desrosiers, Kelledy Manson, and Michael Wyand for
providing samples from SIV-infected animals, Michael Briskin and Meryl
Forman for the conjugated 47 antibody, and Ron Desrosiers for
helpful discussions and review of the manuscript.
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FOOTNOTES |
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* Corresponding author. Mailing address: New England Regional Primate Research Center, Harvard Medical School, One Pine Hill Dr., P.O. Box 9102, Southborough, MA 01772-9102. Phone: (508) 624-8148. Fax: (508) 624-8172. E-mail: paul_johnson{at}hms.harvard.edu.
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Journal of Virology, September 2000, p. 8762-8766, Vol. 74, No. 18
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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