By
From the * Department of Molecular Microbiology and Immunology, Oregon Health Sciences
University, Portland, Oregon 97201, and the Department of Ophthalmology and Visual Sciences,
and the Department of Pathology, University of Illinois at Chicago, Chicago, Illinois 60612
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Abstract |
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The herpes simplex virus (HSV) infected cell protein (ICP)47 blocks CD8+ T cell recognition
of infected cells by inhibiting the transporter associated with antigen presentation (TAP). In
vivo, HSV-1 replicates in two distinct tissues: in epithelial mucosa or epidermis, where the virus enters sensory neurons; and in the peripheral and central nervous system, where acute and
subsequently latent infections occur. Here, we show that an HSV-1 ICP47 mutant is less neurovirulent than wild-type HSV-1 in mice, but replicates normally in epithelial tissues. The reduced neurovirulence of the ICP47
mutant was due to a protective CD8+ T cell response.
When compared with wild-type virus, the ICP47
mutant expressed reduced neurovirulence
in immunologically normal mice, and T cell-deficient nude mice after reconstitution with CD8+ T cells. However, the ICP47
mutant exhibited normal neurovirulence in mice that
were acutely depleted of CD8+ T cells, and in nude mice that were not reconstituted, or were reconstituted with CD4+ T cells. In contrast, CD8+ T cell depletion did not increase the neurovirulence of an unrelated, attenuated HSV-1 glycoprotein (g)E
mutant. ICP47 is the first
viral protein shown to influence neurovirulence by inhibiting CD8+ T cell protection.
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Introduction |
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Herpesviruses are particularly adept at avoiding detection by CD8+ T lymphocytes. They often express several proteins that can independently block the MHC class I presentation pathway by which antigenic peptides are presented to CD8+ T cells. This immune evasion might be particularly important to a family of viruses that persists or establishes latent infections, often for the lifetime of an infected individual. During reactivation from the latent state, herpesviruses encounter robust, fully primed immune systems. Thus, immune evasion is probably important to reduce the effects of antiviral immunity until progeny can be produced. Herpes simplex virus (HSV)1 infected cell protein (ICP)47 blocks the transporter associated with antigen presentation (TAP), so that antigenic peptides cannot be transported into the endoplasmic reticulum, the site of assembly of MHC class I molecules (1). Another human herpesvirus, human cytomegalovirus, encodes at least five polypeptides that each independently inhibit the MHC class I presentation pathway (6). To explain this apparent redundancy, it has been suggested that these viral gene products can act in distinct tissue types to provide resistance to CD8+ T cells (5, 8). However, this has not been tested and in no case has an in vivo effect of one of these herpesvirus proteins been established.
We used a murine ocular model of HSV infection to test
the effects of ICP47 on viral pathogenesis. This model has
been used extensively to study HSV corneal infection, a
disease that is still a leading cause of blindness. HSV-1 infection of the cornea leads to virus replication and transmission
to several tissues, accompanied by leukocytic infiltration in
the following sequence: (a) lesions develop in the epithelial
layer of the cornea after 2 d, accompanied by predominantly PMN infiltration. These lesions heal within 2-3 d in
both immunologically normal and T cell-deficient mice
(12), suggesting that T cells are not important for limiting this primary disease. (b) During infection of the corneal epithelium, sensory neurons that have cell bodies in the
trigeminal ganglia become infected. In ganglia, HSV-1 replication can be detected in sensory neurons, satellite cells,
and Schwann cells from 2-8 d after infection, but then latency is established in neurons. However, with some strains
of HSV-1, latency is incomplete, and the virus can spread
from ganglia to the central nervous system and cause encephalitis. CD8+ T cells play an important role in controlling the duration of HSV-1 replication in sensory ganglia
and preventing transmission to the central nervous system
(13). (c) About 7 d after infection, mice develop lesions in
the skin surrounding the eyelids. These lesions are significantly exacerbated in T cell-deficient mice (14), and it appears that CD4+ and CD8+, /
TCR+ T cells (15, 16),
and
/
TCR+ T cells (14) are important for protection
from HSV-1 skin lesions. Approximately 10-14 d after infection, inflammation develops in the stromal layer of the
cornea, and is regulated by CD4+ T lymphocytes (17, 18)
through the elaboration of the cytokines IFN-
and IL-2
(19). Therefore, HSV disease in this animal model is
controlled by different T cell subsets in different tissues, but
in the nervous system CD8+ T cells are particularly important.
A major consideration in using the mouse model to
study the effect of ICP47 on HSV pathogenesis is the previous observations that ICP47 inhibits the murine TAP relatively poorly (3, 4, 23). Inhibition of TAP activity in
mouse fibroblasts required ICP47 concentrations 50-100-fold higher than those required to inhibit TAP in human
fibroblasts. These studies might militate against the use of a
mouse model to study the ICP47 effect on virus virulence.
However, our initial studies suggested that an ICP47
HSV mutant was less virulent in the mouse nervous system.
This apparent incongruity may relate to the prominent
protective role of HSV-reactive CD8+ T cells in the peripheral nervous system, and the low levels of MHC class I
expression in the nervous system. Neurons are deficient in
antigen presentation, expressing little or no MHC class I on their surface (24). However, low levels of MHC class I
proteins are expressed in satellite cells and Schwann cells,
which also become infected in sensory ganglia, and class I
may be upregulated by HSV infection of these accessory
cells (25). Therefore, it was reasonable to postulate that
ICP47 might block recognition of HSV-infected host cells
by CD8+ T cells in the nervous system, in a manner that
cannot be discerned in assays involving cultured mouse fibroblasts. Indeed, our current findings support this hypothesis by demonstrating that an HSV-1 ICP47 deletion mutant exhibits dramatically reduced neurovirulence in mice
with functional CD8+ T cells, but normal neurovirulence
in CD8+ T cell-deficient mice.
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Materials and Methods |
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Viruses and Construction of an HSV-1 ICP47-mutant.
The wild-type HSV-1 strain F was obtained from Dr. Patricia Spear, Northwestern University, Chicago, IL. This virus was plaque-purified twice before construction of mutant viruses, and was propagated on Vero cell monolayers. Contruction of an HSV-1 glycoprotein E deletion mutant (F-gECharacterization of Viruses for ICP47 and US11 Expression.
To ascertain whether viruses expressed ICP47 and US11, human R970 cells were infected with wild-type HSV-1 F, F-ICP47Virus Inoculation and Evaluation of Disease.
Female A/J, BALB/c, or BALB/c athymic nude mice (Frederick Cancer Research, Frederick, MD), 6-8 wk of age, were anesthetized by intramuscular injection of 2.0 mg of ketamine hydrochloride (Vetalar; Parke-Davis, Morris Plains, NJ) and 0.04 mg of acepromazine maleate (Aveco Co., Fort Dodge, IA) in 0.1 ml of HBSS. The F strain of HSV-1, F-ICP47HSV Titration in the Infected Cornea.
Groups of 10 mice received unilateral corneal infections with either 105 or 104 PFU of wild-type HSV-1, F-ICP47In Vivo CD8+ T Lymphocyte Depletion.
Groups of A/J mice received intraperitoneal injections of 50 µg of rat mAbs specific for CD8-LD50 Assay in Athymic Nude Mice.
Groups of 6 female BALB/c athymic nude mice received corneal infections with various doses of F-ICP47T Cell Reconstitution of Nude Mice.
The corneas of euthymic BALB/c donor mice were infected with 105 PFU of HSV-1. 5 d later, the mice were depleted of CD4+ or CD8+ T lymphocytes by intraperitoneal injection of 250 µg of mAb to mouse CD4 (clone GK1.5; ATCC) or 50 µg of mAb to CD8- ![]() |
Results |
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Groups
of 10 A/J mice received uniocular corneal infections with
two different doses of wild-type HSV-1 strain F, F-ICP47, or F-ICP47
R. The generation and characterization of the
mutant viruses is shown diagrammatically in Fig. 1, and described in detail in Materials and Methods. 2 d after infection, all mice developed dendritic-shaped corneal epithelial
lesions similar to those observed with wild-type HSV-1
(data not shown). As shown in Table 1, the severity of the
corneal epithelial lesions was dose dependent, and the lesions caused by F-ICP47
were similar in magnitude to
those caused by wild-type and F-ICP47
R when scored by a masked observer. Moreover, the yields of virus from
corneas infected with F-ICP47
, F-ICP47
R, or wild-type HSV-1 did not differ (P = 0.79). At the higher doses
of virus, corneal stromal inflammation and periocular skin
disease were difficult to compare because most mice infected with F-ICP47
R or wild-type HSV-1 died of encephalitis. However, in mice infected with a sublethal dose (104 PFU) of wild-type F, F-ICP47
, or F-ICP47
R, there
was a 50-60% incidence of stromal disease (data not
shown), and the severity of this inflammation did not differ
significantly (P = 0.18, Table 1). An equivalent number of
mice infected with wild-type F, F-ICP47
, or F-ICP47
R
developed vesicular skin lesions surrounding the eye and
these lesions were of a similar magnitude (P = 0.63, Table 1). Therefore, ICP47 does not significantly impact HSV-1
replication and virulence in the eye or in the periocular
skin.
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In contrast to the effects seen in the skin and
eye, the ICP47 mutant was less able to cause neurologic
symptoms and death. In 3 experiments, each involving 10 mice, 80% of the mice infected with wild-type HSV-1 experienced hind limb paralysis and loss of motor coordination along with ruffled fur and obvious weight loss by 10 d,
and 76% succumbed to the infection by day 12 (Fig. 2).
Similarly, 68% of the mice infected with F-ICP47
R
showed neurologic symptoms and 61% died by day 13 (Fig.
2). By contrast, only 24% of the mice infected with F-ICP47
displayed neurologic symptoms and died of the infection
(Fig. 2).
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To determine
if CD8+ T cells were responsible for the reduced neurovirulence of F-ICP47, mice were depleted of CD8+ T cells
by treatment with anti-CD8-
mAb, as described in the Materials and Methods section. This treatment protocol
routinely resulted in >98% depletion of CD8+ cells in LN
as assessed by flow cytometric analysis. As shown in Fig. 2,
CD8+ T cell depletion dramatically increased neurological
disease and mortality in mice infected with F-ICP47
, but
had little effect on the mortality caused by wild-type HSV-1
or F-ICP47
R.
A gE-mutant (F-gE), also derived from the HSV-1 F
strain, is also compromised in its ability to induce encephalitis in immunologically normal mice (27). However,
CD8+ T cell depletion did not increase the neurovirulence
of F-gE
(Fig. 2). Thus, although deletion of several HSV
genes can reduce neurovirulence, ICP47 is unique in that
its effect on neurovirulence is only seen in the presence of
functional CD8+ T lymphocytes.
To determine whether CD4+ T cells contribute to the
reduced neurovirulence, we initially attempted similar in
vivo depletion experiments involving an anti-CD4 mAb,
but these studies were inconclusive because depletion of
CD4+ T cells caused significant reductions in CD8+ T cell
infiltration into ganglia (data not shown). We chose to circumvent this problem by performing adoptive transfers
into athymic nude mice. The LD50 of F-ICP47 (2,014 PFU) was not significantly different from the LD50 of
F-ICP47
R (1,596 PFU) in nude mice (Fig. 3). Thus,
ICP47 does not alter virus replication or neurovirulence in
the absence of T lymphocytes.
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To determine whether CD4+ and CD8+ T cells influenced neurovirulence, highly enriched populations of CD4+
or CD8+ T cells, obtained from the LNs of HSV-infected
mice, were transferred into nude mice. Adoptive transfer
of CD8+ T cells significantly enhanced the survival of
F-ICP47-infected mice, but did not significantly alter
survival of F-ICP47
R-infected mice (Fig. 4). Adoptive
transfer of CD4+ T cells did not significantly influence the
survival of mice that were infected with either virus. These
data clearly establish that ICP47 augments HSV neurovirulence in mice by specifically inhibiting a protective CD8+
T cell response. With ICP47 in place, the F strain of HSV-1 is relatively resistant to the effects of CD8+ cells in the nervous system.
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Discussion |
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CD8+ T cells can potentially recognize the broad array of HSV-1 polypeptides that are produced in virus-infected cells. However, there is substantial evidence that HSV avoids detection by CD8+ T cells, and the anti-HSV CD8+ T cell response is often weak in humans (for review see reference 5). ICP47 is an HSV immediate early protein, expressed very early after infection, that can inhibit CD8+ T cell recognition of infected cells (23). Recent studies have established clearly that ICP47 can bind with high affinity to human TAP and inhibit the transport of peptides into the endoplasmic reticulum (3, 4). The implication of this finding is that ICP47 can inhibit the expression of HSV antigens in the context of MHC class I on the surface of infected cells. This is a potentially important adaptation of the virus to the immune defenses of the host. Unfortunately, the contribution of ICP47 to viral virulence cannot be readily determined in humans. Such studies require an animal model in which both the HSV-1 disease pattern and the protective effect of T lymphocytes is characterized.
The role of T lymphocytes in controlling the multiple
disease manifestations that result from HSV-1 corneal infection are well characterized. CD8+ T cells do not play an
essential role in controlling HSV disease in the cornea or
skin. Corneal epithelial disease is resolved with normal kinetics in the absence of CD4+ and CD8+ T cells (12).
CD4+ T cells regulate corneal stromal inflammation (18,
32). Disease in the skin surrounding the eye, which begins
~7 d after the primary infection in the cornea, is controlled
by CD4+ or CD8+ /
+ TCR T cells (15, 33), and by
/
+ TCR T cells (14). However, in the sensory ganglia
CD8+ T cells apparently play a dominant role in controlling HSV-1 replication and in preventing its transmission to
the central nervous system and subsequent establishment of
lethal encephalitis (13). Thus, it was reasonable to assume
that a viral protein that specifically inhibits CD8+ T cell
function might not dramatically affect HSV-1 disease in the
cornea or skin of the mouse, but might nonetheless influence viral neurovirulence and lethality.
The disease pattern seen in immunologically normal
mice after corneal infection with F-ICP47 HSV-1 was
consistent with the hypothesis that ICP47 confers resistance
to CD8+ T cell responses in the nervous system, but is less
effective in the cornea and skin. ICP47 deletion did not influence the capacity of the virus to replicate in and destroy
corneal epithelial cells. Thus, when compared with the parental F strain or the F-ICP47
R revertant, the F-ICP47
mutant produced corneal epithelial lesions of comparable
severity, and similar virus titers were detected in the infected tissue. Moreover, the F-ICP47
mutant, a rescued version of the mutant, and wild-type HSV-1 all produced
mild skin disease in immunologically normal mice, and severe skin disease in T cell-deficient mice. In contrast to
what was seen at the periphery, the ICP47
HSV caused
little or no neurologic disease and encephalitis, while the
wild-type HSV-1 and the rescued virus killed most animals after causing encephalitis.
Since CD8+ T cells help control virus infection in the
nervous system, one could argue that any HSV mutant that
was "crippled" because it replicated less efficiently, either at
the periphery or in the nervous system, might replicate
better in the absence of CD8+ T cells. Although this is possible, we consider it unlikely for several reasons. First,
HSV-1 thymidine kinase and 34.5 mutants do not cause
neurologic disease or encephalitis in either normal or immunologically compromised mice (34, 35). There are defects in replication of these viruses in cells that constitute
the nervous system, and the inability in these viruses to
replicate is not overcome by removing T cells. Second, we
showed here that a gE
HSV-1 is unable to cause neurologic disease whether or not mice are depleted of CD8+ T
cells. This mutant can replicate normally in neurons and
other cells, but can not spread efficiently from cell to cell,
and spreads poorly from the eye to the brain (27, 36).
Therefore, it is not surprising that CD8+ T cell depletion
cannot rescue this defect. Third, reconstitution with CD4+
T cells did not alter the course of disease caused by ICP47
HSV-1 in nude mice. Protection from lethal HSV-1 infections in mice can be controlled by both CD4+ and CD8+
T cells, and in one study a dominant role for CD4+ cells
was described (16). Therefore, the ICP47
HSV is not just
a "weak" virus with defects in replication that can be overcome by inhibiting host immunity. Instead, it appears that
ICP47 augments neurovirulence by specifically subverting a protective CD8+ T cell response.
The capacity of HSV ICP47 to block CD8+ T cell recognition of infected target cells varies in different species
and in different types of cells from the same species. Thus,
HSV-infected human B cells and HSV-infected mouse fibroblasts are lysed by HSV-specific CTLs, whereas HSV-infected human fibroblasts are not lysed by the same CTLs
(23). Moreover, the inhibitory effect of ICP47 on CTL
recognition of human fibroblasts could be overcome by exposure of these cells to IFN-, presumably through its capacity to augment the basal level of antigen processing and
presentation of these cells (23). These findings suggest that
the capacity of ICP47 to block CD8+ T cell protection of
various HSV-infected tissues is determined by a variety of
factors, including: (a) how efficiently ICP47 inhibits TAP
function in that species; (b) the basal level of antigen processing and presentation in cells of the infected tissue; and
(c) the cytokine milieu within the infected tissue. HSV-1 ICP47 is a relatively poor inhibitor of murine TAP function (3, 4). However, in nervous tissue with impaired capacity to process and present antigens in the context of
MHC class I, even a modest inhibition of TAP function
might have a profound effect on a protective CD8+ T cell
response. Assuming a comparable basal level of antigen processing and presentation in the mouse and human nervous system, one would predict a more profound effect of
ICP47 on HSV-1 neurovirulence in humans due to its increased binding affinity for human TAP.
The mechanism by which CD8+ T cells protect HSV-infected sensory ganglia is not clear. A previous study
showed increased production of MHC class I transcripts in
satellite cells, Schwann cells, and neurons of spinal ganglia
after HSV-1 infection of the skin (24). MHC class I protein
was subsequently expressed on the satellite and Schwann
cells, but not on the neurons. CD8+ T cells infiltrate the
trigeminal ganglia of mice ~7 d after corneal infection
with wild-type HSV-1, and some are seen in direct apposition to satellite cells but not neurons in areas of viral antigen expression (37). We propose that direct interaction with CD8+ T cells might result in destruction of the infected satellite cells, but with simultaneous release by the
CD8+ cells of antiviral cytokines that control HSV-1 replication in nearby neurons. This theory is consistent with the
observations that, (a) the cytokines IFN- and TNF-
can
inhibit HSV replication (38, 39), and (b) these cytokines are
produced in the trigeminal ganglion during acute and latent
infection (37, 40). Thus, HSV-specific CD8+ T cells
could control virus by cytotoxic mechanisms acting on replaceable satellite cells, and by noncytotoxic mechanisms in neurons that cannot be regenerated.
The effect of ICP47 on the pattern of MHC class I expression in HSV-1-infected trigeminal ganglia is currently unknown. By inhibiting the upregulation of MHC class I expression on satellite cells, ICP47 could reduce the effectiveness of the CD8+ T cell response. Alternatively, ICP47 might inhibit the direct interaction of CD8+ cells with infected neurons by contributing to the failure of infected neurons to express MHC class I protein, despite production of MHC class I heavy and light chain RNA. Either of these mechanisms could inhibit CD8+ T cell control of HSV-1 replication in sensory neurons, favoring viral transmission to the brain and induction of lethal encephalitis. Although the mechanism remains unclear, our data clearly establish that HSV ICP47 can inhibit a CD8+ T cell response that prevents lethal encephalitis following from corneal infection.
Wild-type strains of HSV vary markedly in their capacity to induce neurologic disease in mice. Observations in both mice (13, 14, 43, 44) and humans (45) have also established that susceptibility to HSV encephalitis is augmented when the host immune system is compromised. Thus, resistance to encephalitis probably results from a balance between the neurovirulence properties of the infecting virus and the strength of the host immune response. In general, this balance is maintained, as encephalitis is rare in humans. Our studies establish for the first time that HSV can influence this balance by producing a protein, ICP47, that inhibits an important host defense mechanism within the nervous system. Our results show clearly that a viral immune evasion strategy can act in a restricted tissue-specific manner and yet dramatically alter the outcome of disease. In addition, our observations underscore the difficulties associated with extrapolating from in vitro biochemical analyses to in vivo effects on viral disease. Based on studies in mouse fibroblasts, one might have predicted that ICP47 would not influence HSV disease in mice.
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Footnotes |
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Address correspondence to Robert L. Hendricks at his current address, Department of Ophthalmology, Rm. 920, Eye and Ear Institute, University of Pittsburgh Medical Center, 203 Lothrop St., Pittsburgh, PA 15213. Phone: 412-647-5754; Fax: 412-647-5880; E-mail: bobhend{at}vision.eei.upmc.edu
Received for publication 14 August 1997 and in revised form 6 November 1997.
1 Abbreviations used in this paper: gE, glycoprotein E; HSV, herpes simplex virus; ICP, infected cell protein; TAP, the transporter associated with antigen presentation.This work was supported by National Institutes of Health grants EY-05945 (to R.L. Hendricks), and EY-11245 (to D.C. Johnson), Core grant EY-01792 (to R.L. Hendricks); an unrestricted research grant from Research to Prevent Blindness, Inc., New York; and by the Lions of Illinois Foundation, Maywood, IL. R.L. Hendricks is a Research to Prevent Blindness Senior Scientific Investigator.
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