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J Virol, July 1998, p. 5351-5359, Vol. 72, No. 7
Infectious Diseases Division, Department of
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
19104-6073
Received 29 December 1997/Accepted 25 March 1998
Herpes simplex virus (HSV) glycoproteins gE and gI form an
immunoglobulin G (IgG) Fc receptor (Fc Herpes simplex virus (HSV)
establishes latency within sensory ganglia and periodically reactivates
to produce recurrent infections. Latency is one mechanism used by HSV
to evade immune attack, since during latency few if any viral proteins
are produced and the virus remains hidden from the host. But how does
the virus evade host immunity during recurrent infection? Virus can
generally be recovered from lesions for several days after reactivation despite an already primed immune system.
HSV encodes at least 11 glycoproteins (48), several of which
are essential for virus replication since they mediate virus entry or
egress (30, 40, 53). Others are nonessential for replication
in vitro yet are conserved in nature, suggesting an important role in
vivo. Glycoproteins gE and gI are among the nonessential HSV
glycoproteins. gE and gI form a hetero-oligomer complex that functions
as a receptor for the Fc domain of immunoglobulin G (IgG) (5, 32,
33, 41). gE alone acts as a lower affinity IgG Fc receptor
(Fc IgG Fc Initial studies of the HSV Fc gE and gI play an important role in virus spread from cell to cell
(2, 9, 10). This has created an obstacle to investigate the
role of the HSV-1 Fc Cells and antibodies.
African green monkey kidney cells
(Vero) were grown in Dulbecco's modified Eagle's medium supplemented
with 10% fetal bovine serum, 20 µg of gentamicin per ml, and 20 mM
HEPES (pH 7.3). Anti-gE monoclonal antibody (MAb) 1BA10 (17)
and anti-gI MAb Fd69 (39) were previously described. Pooled
human IgG (165 mg/ml) was purchased from the Michigan Department of
Public Health, Lansing. This reagent is prepared by pooling serum from
thousands of normal donors. Characteristics of the pooled human
anti-HSV IgG are as follows: anti-HSV-1 enzyme-linked immunosorbent
assay (ELISA) titer, 1:150,000; anti-gE ELISA titer, 1:30,000, anti-gI
ELISA titer, 1:10,000; neutralizing antibody titer against wild-type or
Fc Viruses.
Wild-type HSV-1 strain NS is a low-passage-number
clinical isolate and was used for the generation of mutant viruses
(18). To construct a gE null virus (NS-gEnull),
the entire gE coding sequence was excised from pCMV3gE-1 with
XbaI and cloned into pSPT18 (14). A 1.1-kb
HpaI-BglII fragment from amino acids 124 to 508 (Fig. 1B) was excised, and the HpaI site was changed to a
BglII site. A 4.3-kb fragment derived from pD6P
(22) containing the Escherichia coli
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vivo Immune Evasion Mediated by the Herpes
Simplex Virus Type 1 Immunoglobulin G Fc Receptor
and
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
R) that binds the Fc domain of
human anti-HSV IgG and inhibits Fc-mediated immune functions in vitro.
gE or gI deletion mutant viruses are avirulent, probably because gE and
gI are also involved in cell-to-cell spread. In an effort to modify
FcR activity without affecting other gE functions, we constructed a
mutant virus, NS-gE339, that has four amino acids inserted
into gE within the domain homologous to mammalian IgG FcRs.
NS-gE339 expresses gE and gI, is FcR
, and
does not participate in antibody bipolar bridging since it does not
block activities mediated by the Fc domain of anti-HSV IgG. In vivo
studies were performed with mice because the HSV-1 FcR does not bind
murine IgG; therefore, the absence of an FcR should not affect
virulence in mice. NS-gE339 causes disease at the skin
inoculation site comparably to wild-type and rescued viruses,
indicating that the FcR mutant virus is pathogenic in
animals. Mice were passively immunized with human anti-HSV IgG and then
infected with mutant or wild-type virus. We postulated that the HSV-1
FcR should protect wild-type virus from antibody attack. Human
anti-HSV IgG greatly reduced viral titers and disease severity in
NS-gE339-infected animals while having little effect on
wild-type or rescued virus. We conclude that the HSV-1 FcR enables
the virus to evade antibody attack in vivo, which likely explains why
antibodies are relatively ineffective against HSV infection.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
R), binding IgG aggregates but not IgG monomers, while the gE-gI
complex acts as a higher-affinity FcR, binding both IgG monomers and
aggregates (6, 12).
Rs are fairly widely distributed among human pathogens. Cells
infected by HSV type 2 (HSV-2) (42), varicella-zoster virus
(36), and cytomegalovirus (37) express
virus-encoded IgG FcRs. Certain protozoa (schistosomes and
trypanosomes) (15, 50) and bacteria (for example,
staphylococci [protein A] and streptococci [protein G]) (7,
47) also express IgG Fc binding proteins. Therefore,
understanding the role of the HSV-1 FcR in immune evasion may have
broad implications for understanding microbial pathogenesis.
R focused on its role in binding
nonimmune IgG (1, 8, 11); however, the FcR preferentially binds anti-HSV IgG by a process called antibody bipolar bridging (16, 51). This occurs when an HSV antibody molecule binds to
its antigenic target by its Fab end and the Fc domain of the same
molecule binds to the HSV-1 FcR. In vitro studies indicate that the
HSV FcR inhibits complement-enhanced antibody neutralization (16), antibody-dependent cellular cytotoxicity
(13), and attachment of granulocytes to the Fc domain of
antibodies on HSV-infected cells (51). These results support
a possible role for the FcR in immune evasion and form the basis for
studying the biologic relevance of the HSV-1 FcR in vivo.
R in pathogenesis, since HSV-1 gE or gI null
viruses are practically avirulent (2, 10, 43), probably
because of their inability to spread. Therefore, to study the role of
the FcR in virulence it was necessary to develop HSV-1 mutant
viruses that are deficient in Fc binding while retaining other gE and
gI functions. Using this rationale, an HSV-1 mutant virus that has a
four-amino-acid insert within the gE IgG Fc binding domain was
generated (3, 14). This FcR virus remained
intact for virus spread at the skin inoculation site in mice and caused
disease comparable in severity to that caused by wild-type and
marker-rescued viruses. In the presence of anti-HSV IgG, the
FcR virus was significantly more susceptible to
antibody attack than FcR+ strains, indicating that the
HSV FcR promotes immune evasion in vivo.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
R mutant virus in the absence of complement, 100 µg/ml. In addition, by Western blot analysis, human anti-HSV IgG
recognizes purified HSV-1 glycoproteins gC, gD, gE, and gH, and in an
immunoprecipitation assay the IgG reacts comparably with wild-type gE
and a mutant form of gE that has four amino acids inserted at position
339. The human anti-HSV IgG nonimmune serum was obtained from HSV-1- and HSV-2-seronegative donors (18) and purified on a protein G affinity column (Sigma Chemical Co., St. Louis, Mo.). Murine anti-HSV
serum was pooled from mice 2 to 4 weeks after recovering from wild-type
HSV-1 flank infection. IgG was purified from serum on a protein A
affinity column (Bio-Rad Laboratories, Hercules, Calif.). The
neutralizing titer of murine anti-HSV IgG in the absence of complement
was 50 µg/ml against wild-type and FcR mutant virus.
-galactosidase gene under the control of the HSV ICP6 promoter was
cloned into the BglII site. The resultant vector contains
374 bp of NS DNA sequences 5' and 225 bp 3' of the
ICP6::lacZ cassette and was used to construct the
gE null virus. The XbaI fragment containing the flanking
sequence vector was isolated, and 750 ng was cotransfected into Vero
cells with 1.0 µg of NS DNA by the calcium phosphate transfection
method. Four hours later, the DNA-calcium phosphate mixture was removed and cells were shocked with 15% glycerol. Cells were harvested when
cytopathic effects were noted in 30 to 40% of cells, and cells were
sonicated to prepare a virus pool. Recombinant gE null virus expressing
-galactosidase was selected by infecting Vero cells and overlaying
with 0.5% agarose, 5.0% fetal bovine serum, and 300 µg of
5-bromo-D-galactopyranoside (X-Gal). Blue plaques were
picked and purified twice in X-Gal agarose overlay and once by limiting
dilution. Virus was purified from supernatant fluids of infected Vero
cells on a 5 to 70% sucrose gradient.
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R activity by using biotin-labeled
nonimmune monomeric IgG, which was incubated with infected cells for 30 min at 4°C and then reacted with strepavidin-phycoerythrin
(4). Viruses positive for immunofluorescence were purified
three times by limiting dilution, and one clone, designated
rNS-gE339, was chosen for further studies.
Southern blots were performed to confirm proper construction of mutant
and rescued viruses. When infected Vero cells reached 100% cytopathic
effects, DNA was extracted and 1.0 µg of DNA was digested with
NruI alone or NruI and XhoI to detect
XhoI linkers in NS-gE339 or
NS-gE406. The blot was probed using a 1.1-kb
HpaI-BglII fragment (Fig. 1B) deleted from gE in
NS-gEnull virus.
Fluorescence-activated cell sorting analysis. Double-label staining was performed to detect gE expression and IgG Fc binding. Vero cells were infected at a multiplicity of infection of 5 for 16 h and harvested by using cell dissociation buffer (Gibco BRL, Grand Island, N.Y.). Cells were incubated for 60 min at 4°C with anti-gE MAb 1BA10 and biotin-labeled nonimmune monomeric human IgG (50 µg/ml). Cells were washed and then incubated with fluorescein isothiocyanate (FITC)-conjugated goat F(ab')2 anti-mouse IgG and strepavidin-phycoerythrin for 60 min at 4°C, fixed in 1% paraformaldehyde, and analyzed by dual-channel immunofluorescence (FACScan; Becton Dickinson). To detect gI expression, infected Vero cells were incubated with anti-gI MAb Fd69 (39) and FITC-conjugated goat F(ab')2 anti-mouse IgG.
Complement-enhanced antibody neutralization. Assays were performed by incubating 104 to 105 PFU of wild-type or mutant viruses with anti-HSV pooled human IgG at a concentration (100 µg/ml) that neutralized 50% of the virus in the absence of complement (16). Ten percent human serum obtained from an HSV-1- and HSV-2-seronegative donor, or heat-inactivated serum as a control, was added as source of complement for 60 min at 37°C, and titers were determined by plaque assay on Vero cells. Complement-enhanced antibody neutralization results are expressed as titer (log10) when virus is incubated with antibody plus heat-inactivated complement minus titer (log10) when virus is incubated with antibody plus active complement.
Murine flank model. The shaved right flanks of 5- to 6-week-old female BALB/c mice were denuded by using a depilatory cream. Twenty-four hours later, virus (5 × 103 to 5 × 105 PFU) in 10 µl of sterile Dulbecco modified Eagle medium was applied to the denuded flank several millimeters from the spinal column and scratched gently 30 times with a 27-gauge needle in an approximate 3- by 3-mm area (45, 46). Disease scores were recorded daily and expressed as the sum of the scores from days 3 to 8 postinfection. Disease at the inoculation site was scored as follows: 0 points for no disease; 0.5 for swelling without vesicles; 1.0 point for each vesicle or scab to a maximum daily score of 5 points. If vesicles or scabs became confluent, points were assigned based on the size of the confluent lesion. Swelling and lesions at locations separate from the site of inoculation were considered dermatomal or zosteriform lesions. Scoring of these lesions was the same as at the inoculation site except that a maximum daily score of 10 was used since a larger number of lesions could be counted over the greater skin area involved.
Mice were passively immunized intraperitoneally (44, 46) with pooled human anti-HSV IgG, murine anti-HSV IgG, or nonimmune human IgG 16 h prior to flank infection. Animals were scored for disease at the inoculation and zosteriform spread sites. Passive transfer experiments were performed with 200, 500, or 2,000 µg of IgG/mouse, concentrations which were selected based on previous reports using human antibodies for passive protection (24).Viral titers of skin lesions.
Mice were euthanized, and a
0.5-cm2 area of skin was excised from the inoculation site
1, 2, 3, or 5 days postinfection and stored at 
70°C. Skin samples
were thawed and Dounce homogenized, and virus titers were determined on
Vero cells.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Characterization of HSV-1 gE mutant viruses.
We previously
reported that gE mutant viruses NS-gEnull and
NS-gE339 are FcR, and that
NS-gE339 has a cell-to-cell spread phenotype similar to
that of wild-type virus in epidermal keratinocyte (HaCaT) cells (52). We now report results that confirm proper construction of gE null virus NS-gEnull, gE mutant viruses
NS-gE339 and NS-gE406, and gE rescued viruses
rNS-gEnull and rNS-gE339, and we define the
importance of the HSV-1 FcR in immune evasion by examining in vitro
and in vivo characteristics of NS-gE339.
NS-gE339 is a gE+ gI+
FcR mutant virus.
A number of
FcR viruses have been studied previously (2, 9,
10); however, mutant viruses were gE null, which complicates efforts to separate FcR activity from other functions mediated by
gE. Double-label flow cytometry was performed to measure both FcR
activity and gE expression at the surface of cells infected with
wild-type, gE mutant, or rescued viruses (Fig.
2). NS expresses gE and binds IgG (Fig.
2A). NS-gEnull does not express gE or bind IgG (Fig. 2B).
NS-gE339 expresses gE but does not bind IgG (Fig. 2C),
indicating that this mutant virus is gE+
FcR. This was anticipated since the mutation was
created within the gE Fc binding domain (Fig. 1B). NS-gE406
expresses gE and binds IgG (Fig. 2D), indicating that this mutant virus
is gE+ FcR+, which was expected since the
mutation was outside the gE Fc binding domain (Fig. 1B).
rNS-gEnull expresses gE and binds IgG (Fig. 2E), indicating
rescue of gE null. rNS-gE339 expresses gE and binds IgG
(Fig. 2F), indicating rescue of the FcR phenotype. We conclude that
NS and our panel of mutant and rescued viruses have the expected gE and
Fc binding phenotypes. Our previous studies demonstrated that both gE
and gI are required to bind nonimmune monomeric IgG (12).
Therefore, NS-gE339 gI expression was measured at the
surface of infected cells by flow cytometry and was found similar to
expression of wild-type and rescued virus (not shown), which indicates
that the phenotype of mutant virus NS-gE339 is gE+ gI+ FcR.
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NS-gE339 is defective in antibody bipolar
bridging.
We previously showed that an FcR mutant
virus is not capable of antibody bipolar bridging (16).
Thus, FcR virus or virus-infected cells are more
susceptible to activities mediated by the IgG Fc domain, including
complement activation and antibody-dependent cellular cytotoxicity
(13, 16). We tested whether FcR virus
NS-gE339 is capable of antibody bipolar bridging by
measuring its susceptibility to complement in an assay that detects
complement-enhanced antibody neutralization (Fig.
3A). To this end, 104 to
105 PFU was incubated with human anti-HSV IgG and active
complement, or heat-inactivated complement as a control, and the
neutralization mediated by of the addition of complement was measured.
Human anti-HSV IgG was used at a concentration of 100 µg/ml, which
was the titer that neutralized 50% of each virus strain.
FcR+ viruses NS, rNS-gE339, and
rNS-gEnull showed only 0.2- to 0.5-log10 (2- to
3-fold) additional neutralization when complement was added to human
HSV antibodies, while FcR viruses NS-gE339
and NS-gEnull demonstrated 2- to 2.1-log10
(100- to 126-fold) additional neutralization in the presence of
complement (P < 0.01, FcR viruses
compared with the FcR+ strains) (Fig. 3B). As controls,
viruses were incubated with antibody or complement but not both.
Differences in neutralization among the viruses emerged only when
viruses were incubated with antibody plus complement. As an additional
control, viruses were incubated with murine anti-HSV IgG. The HSV-1
FcR binds the Fc domain of human, but not murine, IgG
(31); therefore, the viral FcR should not protect against
complement-enhanced antibody neutralization using murine IgG as the
source of antibody (16). When the panel of viruses was
incubated with murine antibody plus complement, no differences were
detected among the viruses (result not shown). Therefore, we conclude
that the four-amino-acid insert in NS-gE339 renders the
virus incapable of antibody bipolar bridging and that the
NS-gE339 mutant virus is as susceptible to
complement-enhanced antibody neutralization as is NS-gEnull
virus.
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NS-gE339 causes disease at the inoculation site in the
mouse flank model.
Previous studies showed that gE null viruses
are virtually avirulent (43), likely because gE is required
for virus spread (2, 10). Our intent was to develop an
FcR mutant virus that remained intact for cell-to-cell
spread so that we could separate the multiple functions mediated by gE. We hypothesized that experiments using mice may enable us to separate FcR and cell spread functions, since murine IgG Fc does not bind to
the HSV FcR (31). Therefore, the absence of an FcR
should have no impact on disease in mice.
R virus NS-gE339 was scratched onto the
flanks of mice, and the skin lesions at the inoculation site were
counted. At an inoculum of 5 × 105 PFU,
NS-gE339 produced disease scores comparable to those of NS,
NS-gE406, and rNS-gE339, while
NS-gEnull produced few lesions (each virus compared with
NS-gEnull, P < 0.001) (Fig.
4A). Additional experiments were
performed with wild-type, NS-gE339, and
rNS-gE339 viruses to determine if NS-gE339
produced comparable disease scores over a range of inocula. Figure 4B
demonstrates that disease scores were similar for the three viruses
when inoculated at 10- and 100-fold-lower doses. We conclude that
FcR mutant virus NS-gE339 differs from
previously described gE mutants since it produces disease similar to
those produced by wild-type and rescued viruses at the inoculation
site.
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R mutant NS-gE339
produced zosteriform lesions (at 5 × 105 PFU,
NS-gE339 lesion scores were 21.5 ± 3.5 compared with
NS-gEnull score of 0; P < 0.001); however,
NS-gE339 caused less disease than NS, NS-gE406,
or rNS-gE339 (NS scores were 41.5 ± 1.8, NS-gE406 scores were 37.3 ± 1.6, and
rNS-gE339 scores were 38 ± 1.9; P < 0.01 compared with NS-gE339). Thus, NS-gE339 is
intact for cell spread at the skin inoculation site; however, the virus
may be partially defective in neuronal spread. In support of a possible neuronal spread defect is the observation that zosteriform lesions developed on average 1.3 to 1.4 days later in animals infected with
NS-gE339 than rNS-gE339 or NS. We conclude that
NS-gE339 is a gE+ gI+
FcR mutant virus that is defective in antibody bipolar
bridging but capable of causing disease scores similar to those of
wild-type and rescued viruses at the inoculation site. By focusing on
inoculation site disease rather than on zosteriform spread disease, we
are now able to evaluate the role of the HSV-1 FcR in immune evasion without confounding interpretation of results because of defective cell
spread.
Passive transfer of IgG.
A second set of murine experiments
was performed to evaluate the hypothesis that the HSV FcR is
critical in pathogenesis because it mediates immune evasion. The
experiments involved passive transfer of human anti-HSV IgG into mice
and then infecting the mice with FcR or
FcR+ virus. These studies take advantage of the fact
that human anti-HSV IgG is capable of binding to the HSV FcR by
antibody bipolar bridging (16). We postulated that
FcR virus should be more readily inhibited by human
anti-HSV IgG because the Fc domain of the antibody molecule would be
available to mediate activities such as complement-enhanced antibody
neutralization, antibody-dependent cellular cytotoxicity, and
complement-dependent cellular cytotoxicity.
R virus NS-gE339
or FcR+ virus NS or rNS-gE339. Prior to
infection, mouse serum was tested for neutralizing antibody titers. An
intraperitoneal inoculation of 2,000 µg of anti-HSV IgG resulted in
antibody neutralizing titers of 1:16 in the absence of complement,
while an inoculum of 200 µg produced titers of <1:8. Passive
transfer of antibody at each IgG concentration had little effect on
FcR+ viruses; however, antibody significantly reduced
disease scores in animals infected with FcR virus and
passively immunized with 200 µg of human anti-HSV IgG (P < 0.0001, NS-gE339 compared with NS or
rNS-gE339) or 2,000 µg of human anti-HSV IgG
(P < 0.001, NS-gE339 compared with NS or
rNS-gE339) (Fig. 5A). We
conclude that HSV antibody is significantly more effective in reducing
disease scores of FcR than FcR+
viruses.
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R than
FcR+ viruses. The IgG Fc domain of nonimmune IgG can
bind to the HSV-1 FcR; however, the Fab domain does not bind to HSV
antigens, and therefore nonimmune IgG is not capable of bipolar
bridging. Nonimmune IgG had little effect on disease (Fig. 5B). Since
nonimmune human IgG did not modify HSV-1 disease, we conclude that a
more important function of the HSV-1 FcR is to block activities of
the Fc domain of anti-HSV IgG.
As an additional control, mice were passively immunized with murine
anti-HSV-1 IgG inoculated at 200 or 2,000 µg/mouse. This antibody is
also not capable of antibody bipolar bridging because the Fc domain of
murine IgG does not bind to the HSV-1 FcR (31). We
postulated that murine anti-HSV IgG would have equal effects on
FcR and FcR+ viruses. Results shown in
Fig. 5C support our hypothesis. We conclude that the role of the HSV-1
FcR is to protect the virus or virus-infected cell against human
anti-HSV IgG.
To further demonstrate a role for the HSV-1 FcR in immune evasion,
viral titers were performed on skin excised from the inoculation site.
Animals were passively immunized with human anti-HSV IgG at 500 µg/animal, or saline as control, and then infected with wild-type or
NS-gE339 virus (Fig. 6A). NS
and NS-gE339 viruses grew to similar titers in saline
control animals, which indicates that there is no defect in
NS-gE339 replication in skin. Anti-HSV IgG had little
effect on NS titers but had a dramatic effect on NS-gE339
titers. By day 1 postinfection, NS-gE339 titers were approximately 10-fold lower in antibody-treated animals than in saline
controls, and by day 3, differences in titers reached approximately 10,000-fold (P < 0.01). Virus titers at day 3 were
also measured in animals infected with rescued strain,
rNS-gE339. Virus titers in saline-treated controls were 5.2 log10 ± 0.1 (1.6 × 105 PFU/ml), compared
with 4.6 log10 ± 0.1 (4 × 104 PFU/ml) in
animals treated with human anti-HSV IgG (mean ± standard error of
the mean [SEM] of four animals each). Thus, the rescued strain showed
fourfold differences in titers between antibody-treated and untreated
animals. This contrasts sharply with the FcR mutant
strain, which showed 10,000-fold differences. Additional studies
comparing the effects of murine anti-HSV IgG on virus titers in animals
infected with FcR mutant or rescued virus were
performed (Fig. 6B). At 3 days postinfection, murine anti-HSV IgG had
similar effects on the two virus strains, showing an approximate
2-log10 decrease in titers. We conclude that the FcR
provides marked protection to the virus or infected cell against human,
but not murine, anti-HSV IgG.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Studies to define the biological relevance of the HSV-1 FcR
have been hampered by the fact that gE null viruses are markedly attenuated in vivo, probably because of defects in cell spread. The
approach in the present study was to alter only a small region within
the gE IgG Fc binding domain so that we could isolate an FcR mutant virus that retains other functions mediated
by gE. We constructed gE mutant virus NS-gE339, which has
the following phenotype: gE+, gI+, negative for
binding nonimmune monomeric IgG, negative for antibody bipolar
bridging, and intact for producing lesions at the skin inoculation
site. Therefore, FcR mutant virus NS-gE339
has the phenotype required for in vivo studies to define the role of
the HSV-1 FcR in pathogenesis.
In prior experiments using cells transfected with gE linker insertion
plasmids, we found that plasmid H339 did not form an FcR, whereas
cells transfected with plasmid H406 expressed an FcR (3,
14). When these mutant genes were introduced into the HSV genome,
the resulting HSV-1 virus, NS-gE339, failed to demonstrate
FcR activity, while NS-gE406 had FcR activity similar to wild-type activity. These results indicate that the FcR
phenotypes of gE linker insertion plasmids H339 and H406 were
maintained when recombined into virus.
The mutation at gE amino acid 339 causes loss of FcR activity. This
mutation lies within a cysteine-rich region of the molecule (Fig. 1B),
which could raise concerns about whether the gE protein was grossly
malformed. However, we believe that the mutation disrupts the FcR
domain, as intended, for the following reasons. (i) The mutation at
position 339 is within the gE domain homologous to the site on
mammalian FcRII that binds IgG (14, 28), suggesting that
this region is involved in IgG Fc binding. (ii) Prior studies using
gD-gE fusion proteins demonstrated that a gE domain from amino acid 183 to 402 binds IgG (14). This includes the cysteine-rich domain of gE, which suggests that amino acids in this region form the
FcR. Therefore, the mutation at position 339 is likely to be within
the Fc binding domain. (iii) In NS-gE339, gE is expressed on the virus and at the infected cell surface. If the protein were
grossly malfolded, we would not expect gE transport to remain intact.
(iv) A four-amino-acid mutation at position 380, which is outside the
cysteine-rich region, has been recombined into virus, and this mutant
strain is also FcR (18a). This suggests
that gross alterations in structure are not required to disrupt FcR
activity. (v) NS-gE339 causes disease similar to that
caused by wild-type virus in skin, while NS-gEnull does
not. If the mutation at 339 had grossly altered gE conformation, we
would not expect virulence to remain intact in skin (2). Therefore, we conclude that the mutation at position 339 alters FcR
activity because it disrupts the Fc binding domain.
Studies were performed with mice by using passive transfer of human
anti-HSV IgG to determine if the HSV-1 FcR protects against antibody
attack. Based on in vitro results that demonstrated that FcR+ viruses are capable of binding to and inhibiting
activity of the IgG Fc domain, we postulated that passively transferred
antibodies would have a greater effect on FcR than
FcR+ virus in vivo. Our results showed highly
significant reduction in disease caused by FcR virus
NS-gE339 compared with FcR+ viruses NS and
rNS-gE339. Results of passive transfer experiments using
murine anti-HSV IgG or nonimmune human IgG further supported the
hypothesis that the FcR protects by blocking Fc-mediated activities.
Neither murine anti-HSV IgG nor human nonimmune IgG is capable of
bipolar bridging. The former binds only by its Fab domain to HSV
antigens, while the latter binds only by its Fc domain to the HSV
FcR. Murine anti-HSV IgG inhibited disease scores of
FcR and FcR+ viruses in vivo to
comparable extents, which supports the interpretation that antibody
bipolar bridging accounts for the greater effects of human anti-HSV IgG
on FcR virus. Nonimmune human IgG had no effect on
FcR virus NS-gE339. This was expected,
since this virus cannot bind IgG; however, the lack of effect on
FcR+ virus indicates that binding of nonimmune human IgG
to the HSV-1 FcR has no apparent impact on virulence.
Virus titers were measured in skin samples to support the conclusion
that the HSV-1 FcR promotes immune evasion. We noted marked
differences in virus titers in skin of mice passively immunized with
human anti-HSV IgG and infected with FcR virus. By day
3, NS-gE339 titers were 10,000-fold lower in animals immunized with human anti-HSV IgG compared with saline controls. In
contrast, anti-HSV IgG had little effect on wild-type virus titers,
since only small differences were detected between antibody-treated and
saline controls and these differences were not detected until day 5 postinfection. Titers of the two viruses were similar in saline-treated
controls, which indicates that the differences between NS and
NS-gE339 cannot be explained by defective
NS-gE339 cell-to-cell spread in skin. As controls, virus
titers were also measured at the inoculation site 3 days after
infection of animals passively immunized with murine anti-HSV IgG. As
expected, murine antibody had similar effects on FcR+
and FcR viruses. Therefore, differences in animals
treated with human anti-HSV IgG are attributable to the effects of the
HSV-1 FcR in modifying IgG Fc-mediated activity.
A role for gE in epidermal spread is supported by the findings that gE null virus produces little disease at the inoculation site and small plaques in epidermal cells (52). In contrast, NS-gE339 is intact for epidermal spread, since virus skin titers, inoculation site disease scores, and epidermal cell plaque size (52) are comparable to those for wild-type virus. However, NS-gE339 causes less zosteriform spread disease than wild-type virus, suggesting that the mutant virus may be defective in epidermal-neuronal spread, neuronal transport, or transneuronal spread. Therefore, the gE domain interrupted by the mutation at position 339 disrupts spread in some cell types without affecting others, which suggests that different gE domains may mediate epidermal and neuronal spread.
Additional immune evasion strategies have been described for HSV-1.
Glycoprotein gC binds complement components C3 and its enzymatic
cleavage products, C3b, iC3b, and C3c (17, 34). gC prevents
the interaction of properdin with C3b (29), and blocks C5
interaction with C3b (19, 34). These activities inhibit
activation of the complement cascade, thereby protecting HSV-1 from
complement-mediated neutralization (18, 21, 25, 38) or
HSV-infected cells from complement-mediated injury (23). ICP47 is an immediate-early HSV-1 protein that interferes with the TAP
(transporter associated with antigen processing) system, preventing HSV
peptides from being expressed within the context of major
histocompatibility complex class I antigens (20, 26, 49,
54). ICP47 inhibits peptide expression in human but not mouse
cells (49, 54), while gC, gE, and gI also show species specificity for human immune proteins (18, 27, 31). Proof that immune evasion is important in vivo has been hampered by the
species specificity of the interactions between viral proteins and the
immune system. To circumvent this, the approach taken in this study was
to passively transfer human IgG into mice, which enabled an assessment
of the importance of human IgG-FcR interactions in pathogenesis.
Results of this study help explain why antibodies are relatively
ineffective in modifying HSV infection; however, the experiments do not
address which aspects of IgG Fc-mediated immunity, such as complement
activation, antibody-dependent cellular cytotoxicity, or
complement-dependent cellular cytotoxicity, are inhibited by the HSV-1
FcR. Our results suggest that virus neutralization in the absence of
complement does not account for the effects of antibodies, since serum
obtained from mice passively immunized with human anti-HSV IgG at 200 µg per mouse had a neutralizing titer of <1:8; nevertheless, this
concentration had a marked effect on disease scores and viral titers of
NS-gE339 virus.
The passive transfer murine model mimics conditions that exist
following HSV vaccination, in that antibodies are present prior to
infection. A modification of the model can be used to more closely
simulate conditions during reactivation infection by delaying passive
immunization with anti-HSV IgG until virus reaches the ganglion. Rabbit
corneal infection can also be used to define the role of the FcR in
reactivation disease, since virus reactivates spontaneously in this
model (35), and passive transfer of IgG is not necessary
because rabbit IgG Fc binds to the HSV-1 FcR (31).
However, studies of reactivation disease will require an
FcR mutant virus that is intact for spread from
ganglion to skin so that the role of gE in FcR activity and cell
spread can be clearly distinguished. The experiments performed in this
study define a role for the HSV-1 FcR in antibody evasion but do not address whether the FcR is most important during primary or
reactivation infection.
The fact that the HSV-1 FcR blocks the effectiveness of antibodies
administered prior to infection raises important questions regarding
vaccine strategies to prevent HSV disease. Will the HSV-1 FcR reduce
the effectiveness of vaccine-induced antibodies? If so, attempts to
block HSV-1 immune evasion may require that gE and/or gI be included in
a subunit vaccine. Vaccine strategies to block HSV FcR activity may
be difficult to develop, since despite the high titers of antibodies to
gE and gI in the pooled human IgG used for passive transfer studies,
the antibodies did not effectively block FcR activity of wild-type
virus. This was apparent in complement-enhanced antibody neutralization
experiments that used pooled human IgG and in antibody passive transfer
studies. In these experiments pooled human IgG did not block FcR
activity since FcR+ virus did not escape antibody
attack. Critical epitopes involved in forming the HSV FcR may be
inaccessible to the immune system, or perhaps the epitopes are
immunologically privileged because of sequence homology with mammalian
FcRs.
| |
ACKNOWLEDGMENTS |
|---|
The first two authors contributed equally to this work.
This work was supported by NIH grant AI 33063.
We thank Stuart Isaacs and Ronald Collman for thoughtful comments on the manuscript and Cindy Friedman for help with the artwork.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: 536 Johnson Pavilion, University of Pennsylvania, Philadelphia, PA 19104-6073. Phone: (215) 662-3557. Fax: (215) 349-5111. E-mail: hfriedma{at}mail.med.upenn.edu.
Present address: Adelphi University, Biology Department, Garden
City, NY 11530.
Present address: c/o Robert L. Martuza, Molecular Neurosurgery
Laboratory, Georgetown Medical University, Washington, DC 20007.
§ Present address: Department of Surgery, Philadelphia, PA 19104-6073.
Present address: SmithKline Beecham Biologicals, B-1330 Rixensart,
Belgium.
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REFERENCES |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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