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Journal of Virology, December 1998, p. 10275-10280, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Vaccine Protection against a Heterologous,
Non-Syncytium-Inducing, Primary Human Immunodeficiency Virus
Marjorie
Robert-Guroff,1,*
Harvinder
Kaur,1
L. Jean
Patterson,1
Michel
Leno,1
Anthony J.
Conley,2
Philip M.
McKenna,2
Phillip D.
Markham,3
Ersell
Richardson,1
Kristine
Aldrich,1
Kamalpreet
Arora,1
Lalita
Murty,1
Lucretia
Carter,1
Susan
Zolla-Pazner,4 and
Faruk
Sinangil5
Basic Research Laboratory, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
20892-42551;
Merck Research
Laboratories, West Point, Pennsylvania
194862;
Advanced BioScience
Laboratories, Inc., Kensington, Maryland
20895-10783;
VA and NYU Medical
Centers, New York, New York 100104; and
Chiron Corporation, Emeryville, California
94608-29165
Received 29 June 1998/Accepted 9 September 1998
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ABSTRACT |
Vaccine-induced protection of chimpanzees against
laboratory-adapted and syncytium-inducing, multiply passaged primary
human immunodeficiency virus type 1 (HIV-1) isolates, but not against non-syncytium-inducing, minimally passaged ones, has been
demonstrated. Following challenge with such an isolate,
HIV-15016, we obtained complete protection in one of three
chimpanzees previously protected against low- and high-dose
HIV-1SF2 exposures after immunization with an
adenovirus-HIV-1MN gp160 priming-HIV-1SF2
gp120 boosting regimen. At challenge, the protected chimpanzee
exhibited broad humoral immunity, including neutralizing antibody
activity. These results demonstrate the potential of this combination
vaccine strategy and suggest that vaccine protection against an HIV
isolate relevant to infection of people is feasible.
| |
TEXT |
A combination vaccine approach
consisting of intranasal priming with adenovirus (Ad)-human
immunodeficiency virus type 1 strain MN (HIV-1MN)
gp160 recombinants followed by intramuscular boosting with CHO
cell-expressed HIV-1SF2 gp120 was previously shown to protect chimpanzees against low- and high-dose HIV-1SF2
intravenous (i.v.) challenges with only a minimal number of
immunizations (24). High-dose protection was associated with
long-lived antibodies which persisted for over a year following the
last immunization and were capable of neutralizing both primary and
laboratory-adapted HIV-1 isolates (24, 37). While all
immunized chimpanzees developed cytotoxic T-lymphocyte (CTL) responses,
one lacking neutralizing antibody nevertheless was completely protected
against the low-dose challenge and exhibited a reduced viral burden
following the high-dose challenge. Thus, a role for HIV-specific CTLs
in vaccine-induced control of the viral load in chimpanzees was
suggested. Mucosal immune responses in the form of antibodies in
secretory fluids were also seen following immunization. Together with
results of earlier immunogenicity studies in dogs and chimpanzees
(23, 29, 30) and recently observed immune responses in
rhesus macaques following Ad host range mutant simian immunodeficiency
virus (SIV) env recombinant priming and SIV gp120 boosting
(7), these findings suggest that the Ad recombinant-subunit
boost approach provides a vaccine with the ability to stimulate
production of a complete set of humoral, cellular, and mucosal immune responses.
To pursue these promising results, we decided to challenge the three
previously protected chimpanzees a third time, with the heterologous
primary isolate HIV-15016. Because of its
non-syncytium-inducing (NSI) phenotype, established by lack of
syncytial formation in MT2 cells (19), and its clade B V3
loop consensus sequence (10), the 5016 isolate is more
representative of U.S. clinical isolates than the other available
heterologous challenge isolate, the laboratory strain
HIV-1IIIB. Moreover, the 5016 challenge stock,
developed after only three passages in human peripheral blood
mononuclear cells (PBMCs), gives a robust, persistent infection of
chimpanzees. Two naive chimpanzees exhibited viral loads of
>106 RNA copies/ml of plasma within 4 weeks of i.v.
infection with 30,000 50% tissue culture infective doses
(TCID50) (10). Vaccine-induced protection
against such a minimally passaged NSI isolate has not previously been
shown. A demonstration of protective efficacy against
HIV-15016 would further validate our vaccine approach and
establish the feasibility of preventing transmission of an isolate
relevant to infection of people.
In vivo titration of HIV-15016 challenge
stock.
Prior to the challenge experiment, the titer of
HIV-15016 in vivo in two naive chimpanzees was
determined. Infection was assessed by virus isolation and proviral DNA
in PBMCs as previously described (24) and by
determination of the level of viral RNA in plasma (33).
Chimpanzee 1197, exposed i.v. to 300 TCID50, became
infected and exhibited the expected viral burden of 104 RNA
copies/ml of plasma within 4 weeks (Fig.
1). Persistent infection was demonstrated
post-acute infection by occasional detection of viral RNA in plasma and
the development of low-titer, long-lasting, neutralizing
antibodies. Chimpanzee 941, initially exposed to 3,000 TCID50, exhibited no plasma viral RNA (Fig. 1). Attempts to
isolate virus from or detect proviral DNA in PBMCs were also negative, and the animal did not seroconvert to gag antibodies (not
shown). Exposure of chimpanzee 941 to the same dose 22 weeks later
again failed to infect the chimpanzee. A dose of 30,000 TCID50 given at week 28 was shown necessary to infect this
animal, which over time exhibited a viral burden of 105 RNA
copies/ml of plasma (Fig. 1). Thus, to ensure infection of any naive
control chimpanzee, the challenge dose was established at 30,000 TCID50. Four of four naive chimpanzees have been infected by this dose (reference 10; this report).
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FIG. 1.
In vivo titration of primary isolate
HIV-15016. Chimpanzees 1197 and 941 were inoculated with
the indicated doses of HIV-15016 at the times marked by the
arrows. The viral burden is expressed as RNA copies/milliliter of
plasma as assessed by the nucleic acid sequence-based amplification
technique (33). Titers of neutralizing antibody to
HIV-1MN, expressed as the reciprocal of the serum dilution
at which 50% neutralization was observed, were assessed as previously
described (31), with H9 cells as targets of infection.
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The relative sensitivity of these chimpanzees to in vivo infection
by HIV-1
5016 was not reflected by in vitro studies.
Previously
frozen PBMCs of chimpanzees 1197 and 941 obtained prior
to 5016
exposure were infected in eight replicate microtiter wells with
each of six 10-fold serial dilutions of the 5016 challenge stock
following one cycle of freeze-thawing. Viral infectivity was
determined
by p24 antigen capture assay (National Cancer
Institute-FCRDC,
Frederick, Md.), and the TCID
50 was
calculated by the method of
Spearman-Karber using a computer
software program (
28). The
PBMCs of chimpanzees 941 and
1197 were shown to be equivalently
infectable in vitro by the 5016 isolate (1.3 × 10
4 and 5.6 × 10
4
TCID
50,
respectively).
Reboost and challenge of chimpanzees.
Approximately 3.5 years
had elapsed since initial immunization of the three chimpanzees,
designated 1P, 2PA, and 3P, which were subsequently
protected against low- and high-dose challenges with
HIV-1SF2 (Fig. 2A; reference
24). Because of the length of time with no booster
administrations, at week 187 following their initial immunization, the
three chimpanzees were immunized intranasally with 107 PFU
of each of the three HIV-1MN gp160 recombinants based in Ad4, Ad5, and Ad7 and intramuscularly with 50 µg of CHO-expressed SF2
gp160 in MF59 adjuvant. Replication of the recombinant Ad in nasal
secretions and stool samples was then assessed by nested PCR as
previously described (24), with primers and probes selected from the Ad fiber gene and specific for Ad4, Ad5, or Ad7. Ad titers were subsequently determined by serial 10-fold dilution of positive samples. The sensitivity of the nested PCR technique was
equivalent to 0.1 PFU/10 µl of sample. Serum Ad neutralizing antibody
titers were assessed by a type-specific microneutralization assay
(22).
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FIG. 2.
Immunization and challenge history of the three
previously protected chimpanzees. (A) Prior administrations of one,
two, or three HIV-1MN gp160 recombinants based in Ad4, Ad5,
or Ad7 vectors and one or two boosts with CHO-expressed gp120 of the
HIV-1SF2 strain are listed. The animals were protected
against low- and high-dose HIV-1SF2 challenges at weeks 52 and 98, respectively, with no intervening immunizations
(24). The timing of the boost and challenge described in
this report is outlined in the boxed area. (B) Ad neutralizing antibody
titers following initial and booster immunizations are listed.
Postimmunization peak titers are listed. Duration of Ad shedding in
nasal secretions, expressed in weeks, and peak viral titers of positive
samples, expressed as PFU per milliliter, following the booster
immunization at week 187 are also listed. Ad titers were adjusted for
an ~10-fold dilution of nasal secretions obtained by swabbing. n.a.,
not applicable.
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Following immunization, low-level shedding of Ad-HIV recombinants was
detected in nasal secretions but not in stool samples
of chimpanzees
2P
A and 3P (Fig.
2B). Both animals exhibited up
to sixfold
increases in Ad neutralizing antibody titers, indicative
of Ad
replication in the upper respiratory tract. Previous administrations
of
Ad gp160 recombinants (Fig.
2A) did not necessarily preclude
subsequent
vector replication. However, variability in the response
to Ad
infection is shown by chimpanzee 1P, in which poor replication
was
reflected by low Ad neutralizing antibody titers and a lack
of
detectable Ad shedding (Fig.
2B).
At 189 weeks, the three chimpanzees and naive control chimpanzee C2
were challenged i.v. with 30,000 TCID
50 of
HIV-1
5016.
Chimpanzee 2P
A was completely
protected from 5016 infection. Viral
RNA was not detected in the
animal's plasma for the entire monitoring
period (Fig.
3). The animal remained negative for
virus isolation
and proviral DNA in PBMCs and did not exhibit HIV
gag antibodies
in Western blots (Table
1). In contrast, the other three
chimpanzees
became infected (Fig.
3; Table
1). Control C2 and
chimpanzee
1P had viral burdens of >10
6 RNA copies/ml of
plasma, while chimpanzee 3P exhibited a 10-fold
reduction in peak
plasma viral RNA copy number relative to the
naive animal (Fig.
3).
Identification of virus present in infected chimpanzees.
Because the immunized chimpanzees had been previously exposed to
HIV-1SF2, viral RNA recovered from serum or plasma samples from the infected animals was analyzed to identify the virus
being replicated. RNA was extracted by a guanidine
thiocyanate-N-laurylsarcosine protocol (9). The
envelope V3 region was amplified by using the GeneAmp RNA PCR kit
(Perkin-Elmer Cetus, Norwalk, Conn.) and the
primer 5'-CAUCAUCAUCAUCAAATTCTGGGTCCCCTCCTGA GG-3'
in the reverse transcriptase reaction and the
primer 5'-CUACUACUACUAGCTAAAACCATAATAGTACAGC TG-3'
in the PCR master mix. PCR products were cloned in the pAMP vector
plasmid of the CloneAMP System (Life Technologies, Inc., Gaithersburg,
Md.) and sequenced. Four clones obtained from control chimp C2
exhibited a V3 region sequence identical to that of the predominant
species present in the 5016 challenge stock (Fig. 4). In contrast, six clones obtained from
chimp 1P had a variant V3 loop sequence, suggesting infection by a
minor species present in the 5016 stock. Whether immune selection
played a role in infection by this variant has not been determined. The
V3 loop sequence of the variant differs from that of the SF2 isolate,
indicating that the third viral challenge did not reactivate previously
undetected virus in animal 1P. No clones could be obtained from the
plasma of chimpanzee 3P.
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FIG. 4.
Comparison of V3 region sequences of 5016 challenge
stock with those present in infected chimpanzees.
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Humoral immune responses.
To investigate the basis for the
complete protection of chimpanzee 2PA, numerous immunologic
parameters were examined over time. Neutralizing antibodies in
chimpanzee sera were assessed from week 187 through the postchallenge
period. Chimpanzees 1P and 3P exhibited good neutralizing antibody
titers against laboratory-adapted HIV-1MN at week 187 postimmunization, but these titers were not boosted until after
challenge, reflecting infection (Fig. 5). In contrast, chimpanzee 2PA displayed a dramatic boost in
HIV-specific neutralizing antibodies in response to the immunization,
rising from a titer of 50 to >8,100 at the time of the boost and
challenge, respectively, for the MN isolate and from a titer of <10 to
nearly 300 for the SF2 isolate (Fig. 5; Table
2). All three chimpanzees were able to
neutralize the primary isolate BZ167 at challenge, with chimpanzee
2PA again displaying an increased response after the
booster immunization (Fig. 5; Table 2). Neutralization of HIV-15016 was seen at challenge only in the serum of
chimpanzee 2PA (Table 2), in which antibody activity was at
the threshold of detection as assessed by using
phytohemagglutinin-stimulated human PBMC target cells
(24). By using an infectivity reduction technique
(26), small reductions in viral infectivity were observed for all three chimpanzees but did not reach statistical significance (Table 2). For the comparison of chimpanzee 2PA serum with
that of the control, P was 0.1. The 5016 isolate appears
particularly resistant to in vitro neutralization. Two naive
chimpanzees persistently infected for over a year with 5016 have at
present never developed homologous in vitro neutralizing antibody
activity (10, 27).
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FIG. 5.
Neutralizing antibody responses at boost and following
challenge. Titers of neutralizing antibody to the laboratory isolates,
HIV-1MN and HIV-1SF2, for the three immunized
chimpanzees are expressed as reciprocal serum dilutions. Neutralization
of the primary isolate, BZ167, is expressed as percent neutralization
observed at a 1:20 serum dilution.
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To examine the breadth of the antibody response, we assessed chimpanzee
sera for binding to V3 loop peptides synthesized by
Peptide
Technologies, Inc., Gaithersburg, Md. Peptide sequences
for
the MN, SF2, and 5016 loops were
YNKRKRIHIGPGRAFYTTKNIIGC,
TRKSIYIGPGRAFHTT, and
TRKSIHIGPGRAFY, respectively. Chimpanzee
2P
A serum
exhibited the broadest antibody responses, reacting
with all three
V3 loop peptides tested at the time of challenge
(Fig.
6; Table
2). In contrast, sera of
chimpanzees 1P and 3P
exhibited good reactivity only with the MN
peptide at challenge
(Table
2). Broadening of the antibody response in
chimpanzees
1P and C2 was only observed following infection (Fig.
6).
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FIG. 6.
Binding antibodies to V3 loop peptides at boost and
following challenge. Binding was assessed by peptide enzyme-linked
immunosorbent assay (32) on sera diluted 1:100. Absorbance
values of preimmune sera or prechallenge sera for chimpanzee C2
(ranging from 0.055 to 0.122 for the SF2 peptide, from 0.148 to 0.391 for the MN peptide, and from 0.039 to 0.102 for the 5016 peptide) have
been subtracted from the values presented.
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Cellular immune responses.
CTL activity in chimpanzee
PBMCs was assessed as previously described (24) with, as
target cells, Epstein-Barr virus-transformed autologous chimpanzee B
cells infected with either a vaccinia virus-SF2 envelope recombinant
(11), a vaccinia virus-MN gp160 recombinant (34),
or a vaccinia virus 
-galactosidase recombinant as control
(8). After receiving the booster, only chimpanzee 3P
PBMCs obtained 1 week postboost exhibited significant CTL activity (Fig. 7), which likely resulted from
better replication of the Ad gp160 recombinants. Chimpanzee 3P shed Ad5
and Ad7 gp160 recombinants in nasal secretions for 2 weeks (compared to
only 1 week for chimpanzee 2PA), exhibited a higher titer
of the Ad5 gp160 recombinant shed, and replicated the Ad4 gp160
recombinant while chimpanzees 1P and 2PA did not (Fig. 2B).
The CTL response may have contributed to the decreased viral
burden observed in chimpanzee 3P following challenge (Fig. 3). Although
PBMCs of this animal did not exhibit CTL activity at challenge
(Table 2), we have previously seen CTL activity in tissue T lymphocytes
when similar activity was not apparent in PBMCs (1, 24).
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FIG. 7.
CTL activity observed in chimpanzee PBMCs at boost
and following challenge. CTL activity is shown at the time of the
booster immunization ( 2 weeks postchallenge), 1 week later (1
week), at the time of challenge (0 weeks), and 2 weeks postchallenge.
Data were not recorded if the spontaneous lysis of target cells was
greater than 30%. Values shown are for effector-to-target cell ratios
of 100:1. No lysis of control targets infected with the vaccinia virus
-galactosidase construct over spontaneous levels was observed in
these experiments.
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We also considered that protection might have resulted from
CD8
+ T-cell suppressor activity (
35). Suppressor
activity of positively
selected CD8
+ T cells obtained from
the four chimpanzees at the time of challenge
was assessed in an acute
infection system (
21,
25) using elutriated
human macrophages
as targets of HIV-1
5016 infection. Viral infection
was
monitored by p24 antigen capture assay. Suppressor activity
was high in
chimpanzee 2P
A and control C2 but low in chimpanzees
1P and
3P (Table
2). Therefore, the complete protection of chimpanzee
2P
A was not strictly correlated with this nonlytic,
non-major
histocompatability complex-restricted, CD8
+
antiviral
activity.
In vitro HIV-15016 infection.
Chimpanzee
2PA might have remained uninfected as a result of a natural
resistance to HIV-15016 infection. The ability of
chimpanzee PBMCs to support infection of the 5016 isolate in vitro
was determined with previously frozen cells obtained prior to any
immunization or challenge. PBMCs were thawed, cultured overnight,
and stimulated for 3 days with phytohemagglutinin prior to
infection with serial dilutions of a fourth-passage PBMC stock of
HIV-15016. TCID50 were calculated as
described above for animals 941 and 1197. The results indicated
that all prebleed chimpanzee PBMCs were equivalently infectable.
The TCID50 on cells from protected chimpanzee
2PA was 1.2 × 102. Values on cells of the
other chimpanzees were 6.5 × 102, 7.6 × 102, and 1 × 102 for chimpanzees 1P, 3P,
and C2, respectively. Thus, complete protection of chimpanzee
2PA was not correlated with natural resistance to 5016 infection.
Discussion.
In this study, three previously protected
chimpanzees were challenged a third time to assess the breadth of
protective immunity established by a combination vaccine strategy. The
results, first demonstrating vaccine-induced protection against a
minimally passaged, heterologous NSI primary HIV isolate, support
further development of Ad-HIV recombinants in a bimodal approach for an
AIDS vaccine. Only one of three immunized chimpanzees was protected
against HIV-15016 infection, but the protection was
achieved by using a vaccine regimen based only on the HIV envelope. It
is clear from the work of other groups that vaccines incorporating
additional HIV genes are more effective (18). We expect that
future experiments using multicomponent Ad-HIV recombinants under
development will result in greater protective efficacy.
It is not possible to determine whether the two prior
HIV-1
SF2 challenges contributed to the protection seen in
chimpanzee
2P
A. The previous exposures may have served as
boosts to the immune
system, resulting in greater resistance to
infection than would
have been achieved solely by the immunization
regimen. We can
speculate that in general such natural boosting,
initiated by
a level of vaccine-induced immunity able to protect
against a
first virus exposure, might ultimately provide the basis for
long-lasting
vaccine protection. In any case, a new study will be
required
to assess protective efficacy of our combination vaccine
approach
against an initial HIV-1
5016 challenge. It is
noteworthy, however,
that the immunization regimen used here based on
envelopes of
syncytium-inducing laboratory strains, with or without an
additional
boosting effect by subinfectious HIV-1
SF2
exposure, resulted in
protection against an NSI, primary isolate. The
result suggests
that some common protective mechanisms against
syncytium-inducing
and NSI viruses may
exist.
With regard to the basis for complete protection of chimpanzee
2P
A, the striking rise in antibody titer at the time of
challenge,
the broad antibody reactivity, and the degree of
neutralizing
activity against the 5016 isolate are notable. Whether the
latter,
magnified in the undiluted in vivo environment, was sufficient
to confer protection is not known, and we cannot conclude that
antibody
alone provided the protective mechanism. While neutralizing
antibodies
have been correlated with protection of chimpanzees
against i.v.
challenge (
3,
6,
13,
14,
16,
17) and
probably exert their
greatest influence against this route of
transmission, it is likely
that other factors play a role as well.
CTL activity, while not
observed in PBMCs of chimpanzee 2P
A at
challenge, may
have been sequestered in tissues. In addition,
while not correlated
here with a lack of infection, a high level
of CD8
+
suppressor activity was exhibited by chimpanzee 2P
A at
challenge
and could have contributed to its protection. This
nonlytic non-major
histocompatability complex-restricted inhibitory
activity has
been associated with protection in SIV macaque
models (
20,
21,
36).
Other immunization strategies have shown some success in protecting
chimpanzees from i.v. challenge with cell-free or cell-associated
virus. These include use of subunit immunogens and inactivated
virus
(
2-4,
6,
12,
15-17) and more recent experiments with
DNA
vaccines (
5). At present, the combination Ad recombinant
priming-subunit boosting approach has been most promising in terms
of
duration of protection following few immunizations, the development
of
antibodies able to neutralize both primary and laboratory-adapted
isolates, and most importantly as shown here, protection against
a
representative U.S. clinical isolate of the NSI type believed
responsible for the majority of HIV transmissions between people.
Whether this vaccine regimen will also protect against transmission
via
the highly relevant mucosal route can only be determined following
development of a mucosal challenge stock for
chimpanzees.
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ACKNOWLEDGMENTS |
We thank Michael Lubeck, John Eldridge, and Stephen Udem for
helpful discussion; Ali Javadian and Patrice Frost for carrying out all
aspects of the study directly involving the chimpanzees; John Bisbing,
Michael Justice, and Lina Cuadra for excellent technical assistance;
and Larry Arthur and Genoveffa Franchini for critical reviews of the manuscript.
This study was supported in part by a Cooperative Research and
Development Agreement with Lederle-Praxis Biologicals Division, American Cyanamid Company.
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FOOTNOTES |
*
Corresponding author. Mailing address: Basic Research
Laboratory, National Cancer Institute, National Institutes of Health, Building 37, Room 6B03, Bethesda, MD 20892-4255. Phone: (301) 496-2114. Fax: (301) 496-8394. E-mail:
guroffm{at}dc37a.nci.nih.gov.
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Copyright © 1998, American Society for Microbiology. All rights reserved.
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