(Investigative Ophthalmology and Visual Science. 2000;41:132-137.)
© 2000
by The Association for Research in Vision and Ophthalmology, Inc.
Natural Killer Cells Prevent Direct Anterior-to-Posterior Spread of Herpes Simplex Virus Type 1 in the Eye
Minoru Tanigawa1,3,
John E. Bigger2,
Maria Y. Kanter1 and
Sally S. Atherton1,2
From the Departments of
1 Cellular and Structural Biology and
2 Microbiology, University of Texas Health Science Center at San Antonio; and the
3 Department of Ophthalmology, Kobe University School of Medicine, Japan.
 |
Abstract
|
|---|
PURPOSE. Anterior chamber (AC) inoculation of the KOS strain of herpes simplex
virus type 1 (HSV-1) results in morphologic sparing of the ipsilateral
retina, whereas the retina of the uninoculated contralateral eye
becomes infected and undergoes acute retinal necrosis. Natural killer
(NK) cells are an important component of the primary immune response to
most virus infections. The purpose of this study was to determine
whether NK cells are involved in preventing early direct
anterior-to-posterior spread of HSV-1 after AC inoculation.
METHODS. Normal BALB/c mice were inoculated with 4 x 104
plaque-forming units (PFU) of the KOS strain of HSV-1 using the AC
route. NK activity was measured in the spleen, the superficial cervical
and submandibular lymph nodes, and the inoculated eye by lysis of
chromium-labeled, NK-sensitive YAC-1 target cells. Histopathologic
scoring and immunohistochemical staining for HSV-1 were performed in
NK-depleted (injected intravenously with anti-asialo GM1)
or mock-depleted (injected intravenously with normal rabbit serum)
mice.
RESULTS. In mock-depleted mice, NK activity in the spleens, superficial cervical
and submandibular lymph nodes, and inoculated eyes peaked at
postinoculation (pi) day 5 and declined by pi day 7. Treatment with
anti-asialo GM1 eliminated NK activity in the eye and at
nonocular sites. The histopathologic scores at pi day 5 indicated more
damage to the retinas of NK-depleted mice than to those of
mock-depleted mice, and immunohistochemical staining for HSV-1 showed
spread of the virus to the sensory retina only in NK-depleted mice.
CONCLUSIONS. NK cells were activated within 5 days after AC inoculation of the KOS
strain of HSV-1. Activation of NK cells appears to play a role in
preventing direct anterior-to-posterior spread of the virus in the
inoculated eye which, in turn, protects the retina of this eye and
helps to explain why the architecture of the retina of this eye is
spared.
 |
Introduction
|
|---|
After uniocular anterior chamber (AC) inoculation of the KOS
strain of herpes simplex virus (HSV)-1 in euthymic BALB/c mice,
extensive virus infection accompanied by a massive inflammatory
response is observed in the anterior segment of the injected
eye.1
However, in spite of the virus infection and
inflammation in the anterior segment, HSV-1 does not spread from the
infected AC directly to the retina of the injected eye after uniocular
AC inoculation.2
3
4
Although virus infection and retinitis
are observed in the inoculated eye of T-celldepleted mice, virus
entering the retina of these mice spreads there through retrograde
transport in the optic nerve of the injected eye on or about
postinoculation (pi) day 9.5
Direct anterior-to-posterior
spread of virus is not observed in T-celldepleted mice at any time
after inoculation. Thus, although T cells are involved in preventing
spread of virus to the ipsilateral optic nerve,5
they do
not appear to be responsible for preventing direct
anterior-to-posterior spread of the KOS strain of HSV-1 after uniocular
AC inoculation. Therefore, it is likely that a nonT-celldependent
mechanism prevents spread of virus to the retina of the injected eye.
An early, but nonspecific, mechanism of protection operative in many
types of infections is natural killer (NK) cells.6
NK
cells, a subset of large, granular lymphocytes, are activated by the
cytokines interferon (IFN)-
, IFN-ß, and interleukin (IL)-12 and
can secrete cytokines with antiviral activity such as IFN-
and tumor
necrosis factor (TNF)-
when activated.7
8
NK cells lyse
virus-infected cells after conjugate recognition of those cells by a
major histocompatibility complexunrestricted mechanism. However, the
eye constitutively expresses NK-suppressing factors, including TGF-ß
and macrophage migration inhibitory factor, which have been shown to
diminish NK activity in vitro.9
10
11
12
13
NK cells have been
shown to be important in resistance to a number of primarily
intracellular pathogens, including HSV. Intraperitoneal injection of
HSV increases NK cell activity, and NK cells have been shown to
modulate replication of HSV-1 in the liver and
brain.14
15
16
The purpose of the studies described in this
article was to examine the role of NK cells in the injected eye after
uniocular AC inoculation of HSV-1. The results of these studies suggest
that NK cells prevent direct anterior-to-posterior virus spread of KOS
strain of HSV-1 in the injected eye after uniocular AC inoculation.
 |
Methods
|
|---|
Animals
Female BALB/c mice, 6 to 8 weeks old, were obtained from Taconic
Farm (Germantown, NY). Animals were housed in accordance with National
Institutes of Health guidelines. All animal experiments conformed to
the ARVO Statement for the Use of Animals in Ophthalmic and Vision
Research. Mice were maintained on a 12-hour light-dark cycle and given
unrestricted access to food and water.
Virus
The KOS strain of HSV-1 was used in this study. Virus stocks were
titered on Vero cell (ATCC, Rockville, MD) monolayers, as described
previously.5
Ocular Injection
Mice were anesthetized by intramuscular injection of a cocktail
containing 0.02 ml Rompun (X-JECT 5.A; Uetus Animal Health, St
Joseph, MO) and 0.03 ml ketamine per 25 g body mass. The AC of the
right eye of each mouse was inoculated with 4.0 x 104
plaque-forming units (PFU) of KOS in a volume of 2 µl.
Chromium Release Assay
One million YAC-1 target cells were labeled with 100 µCi
chromium-51 (Du PontNEN, Wilmington, DE) for 1 hour in 500 µl RPMI
1640 with 5% fetal calf serum (RPMI-5) at 37°C. After labeling, the
target cells were washed three times and seeded into 96-well plates at
a concentration of 104 cells/100 µl per well.
Effector cells were obtained from the spleen, the superficial cervical
and submandibular lymph nodes, or the inoculated eye. Splenic effector
cells were prepared by grinding the spleens between frosted slide
glasses, followed by aspiration through a 22-gauge needle to make a
single-cell suspension. Spleen cells were washed three times in Hanks
balanced salt solution (HBSS), and erythrocytes were lysed by ammonium
chloride treatment; the remaining spleen cells were washed three times
in HBSS and resuspended in RPMI-5. Cells from the superficial cervical
and submandibular lymph nodes ipsilateral to the site of injection were
isolated by teasing the tissue through a 200-µm nylon mesh. The cells
were then washed three times and resuspended in RPMI-5. Eyes were
enucleated after cardiac perfusion, and the conjunctiva and extraocular
muscles were removed under the dissecting microscope. The eyes were
teased through a 70-µm mesh, and the cells were washed three times in
HBSS and resuspended in RPMI-5. To have enough effector cells from the
eye for the assays, three or four eyes were collected at each time
point.
Splenocytes, lymph node cells, and ocular cells were counted, and 100
µl per well of the dilution of effector cells needed to give the
appropriate effector-target ratio was plated in triplicate. For
spontaneous release, 100 µl RPMI-5 and for maximum release, 100 µl
10% Triton X-100 (Sigma, St. Louis, MO) were added instead of effector
cells. Plates were incubated for 4 hours at 37°C, and 100 µl of the
supernatant in each well was counted in a gamma counter (Wizard 1470;
Wallac, Turku, Finland). Each set of triplicates was averaged, and the
percentage of specific lysis was determined by the following formula:
% specific lysis = (experimental release - spontaneous
release)/(maximum release - spontaneous release) x 100.
Spontaneous release in all experiments was less than 10% of the
maximum release.
Treatment of Mice with Anti-Asialo GM1 Serum
To deplete NK cell activity in vivo, a 10-fold dilution of
anti-asialo GM1 rabbit serum (Wako Chemicals,
Richmond, VA) was made in sterile phosphate-buffered saline (PBS) and
injected into a tail vein in a volume of 0.1 ml. A single intravenous
injection of this amount of anti-asialo GM1
reduced poly(I-C) activated splenic NK activity to undetectable levels
for 4 days (not shown). This regimen had no effect on the splenic
T-cell populations as determined by flow cytometry (not shown). Control
animals were mock depleted with intravenous injections of the volume
and concentration of normal rabbit serum (Vector Laboratories,
Burlingame, CA). To maintain depletion of NK activity, anti-asialo
GM1 serum was injected intravenously every 4 days
beginning on day -1.
Histopathologic Evaluation of the Retina
Eyes were fixed in buffered formalin, embedded in paraffin, and
sectioned. The sections were then stained with hematoxylin and eosin. A
modification of the semiquantitative histopathologic scoring system
described by Azumi and Atherton5
was used to evaluate the
extent of retinal destruction, inflammatory cell infiltration,
hypercellularity of the choroid, and amount of pyknotic debris as shown
in Table 1
. The maximum possible histopathologic score for a single retina
was 13.
Immunohistochemistry
Mice were killed and perfused with PBS. The eyes were removed,
embedded in Tissue-TEK O.C.T. (optimum cutting temperature)
compound (Miles, Elkhart, IN), and sectioned at 8 µm using a
cryostat. All sections were air dried and stored at -70°C. Before
staining, sections were fixed in acetone for 5 minutes, washed twice
with PBS, and placed in 0.3% hydrogen peroxide in methanol for 15
minutes. Sections were then washed twice with PBS and incubated with
buffered casein solution (PowerBlock; Bio Genex, San Ramon, CA) for 15
minutes. Excess casein solution was blotted, and the sections were
incubated with a 1:200 dilution of rabbit polyclonal anti-HSV-1
antibody (Dako, Carpinteria, CA) for 2 hours. The sections were washed
twice with PBS, incubated with a 1:500 dilution of biotinylated goat
anti-rabbit IgG (Vector) for 45 minutes, washed twice with PBS, and
incubated with Vectastain ABC (Vector), according to the
manufacturers directions. The sections then were washed three times
with PBS and reacted with 0.5 mg/ml 3,3'-diaminobenzidine
tetrahydrochloride solution (Sigma) supplemented with 0.3% nickel
chloride and 0.01% hydrogen peroxide. Color development was monitored
microscopically. All sections were counterstained with methyl green.
 |
Results
|
|---|
Activation of NK Cells in the Spleen, Lymph Nodes, and Eye after AC
Inoculation of HSV-1
After AC inoculation of HSV-1 (KOS) into normal BALB/c mice, the
ipsilateral retina does not become virus infected. Because there is no
anatomic barrier to prevent virus spread within the eye and because T
cells have been shown to protect the inoculated eye by preventing
retrograde spread of virus from the brain,5
a nonT-cell
mechanism, such as NK cells, appears to be responsible for preventing
direct anterior-to-posterior spread of HSV-1 after uniocular AC
inoculation. Injection of HSV-1 into the AC usually results in
induction of anterior chamberassociated immune deviation (ACAID), and
both the aqueous and the vitreous of the eye contain multiple
substances that depress NK activity.9
10
11
12
13
To determine
whether AC inoculation of HSV-1 induces an NK response, the cytolytic
activity of cells from the spleen, lymph nodes, and inoculated eye was
measured by chromium release assays. On day 1, 3, 5, or 7 before the
chromium-release assay, 4.0 x 104 PFU of
HSV-1 was injected into the AC of one eye. On the day of assay, mice
were killed and cells from the spleen, lymph nodes, and inoculated eye
were assayed for cytolytic activity against NK-sensitive YAC-1 target
cells. As shown in Figure 1 , the cytolytic activity of splenocytes (Fig. 1A)
, of cells from the
superficial cervical and submandibular lymph nodes (Fig. 1B)
, and of
cells from the eye (Fig. 1C)
was first detected on pi day 3, peaked on
pi day 5, and returned to baseline on pi day 7. Treatment with
anti-asialo GM1 eliminated NK activity of ocular
cells (Fig. 2)
and splenocytes (not shown).

View larger version (26K):
[in this window]
[in a new window]
|
Figure 1. Cytotoxicity of NK sensitive targets (YAC-1) by splenocytes
(A), superficial cervical and submandibular lymph node cells
(B), or ocular cells (C) after AC inoculation of
HSV-1. Mice were infected using the AC route with 4.0 x
104 PFU of the KOS strain of HSV-1 on days 1, 3, 5, or 7
before assay. Splenocytes (A), superficial cervical and
submandibular lymph node cells (B), or ocular cells
(C) were harvested and single-cell suspensions were prepared
and used in cytolytic assays against chromium-51labeled YAC-1
targets. The results from one representative experiment of three
experiments are shown.
|
|

View larger version (23K):
[in this window]
[in a new window]
|
Figure 2. Elimination of NK cytotoxic activity of ocular cells by treatment with
anti-asialo GM1. Ocular cells were collected on pi day 5
from HSV-1infected BALB/c mice treated with anti-asialo
GM1 or from HSV-1infected mice treated with an equivalent
volume of normal rabbit serum. Ocular cells were also collected from
normal uninfected mice. Single cell suspensions were prepared and used
in cytolytic assays against chromium-51labeled YAC-1 targets.
|
|
Destruction of the Ipsilateral Retina after Inoculation of KOS into
the AC of NK-Depleted Mice
To determine whether the NK response after AC inoculation of KOS
is involved in protecting the retina of the injected eye from viral
infection and subsequent destruction, BALB/c mice were injected
intravenously with anti-asialo GM1 serum or an
equivalent volume and concentration of normal rabbit serum (control
mice) on day -1; on day 0, 4.0 x 104 PFU
of the KOS strain of HSV-1 was injected into the AC of one eye.
Histopathologic scores of the inoculated eyes of NK-depleted mice were
compared with those of the mock-depleted mice. At pi day 3, the retinas
of mice in both groups had only slight atypical retinopathy, and there
was no significant difference between the retinal scores of NK-depleted
and mock-depleted control mice (not shown). However, by pi day 5,
significantly more disease was observed in the retinas of NK-depleted
mice than in the retinas of mock-depleted mice at pi day 5
(P < 0.035; Table 2
). As shown in Figure 3 , destruction of the sensory retina, inflammatory cell infiltration, and
choroidal hypercellularity were observed in retinas of mice in the
NK-depleted group (Fig. 3B)
, whereas in the mock-depleted mice, only
mild retinal folding similar to that previously observed in the
inoculated eyes of normal mice after AC injection of HSV-1 was seen
(Fig. 3A)
.1
5

View larger version (64K):
[in this window]
[in a new window]
|
Figure 3. NK depletion results in destruction of the retina of the injected eye.
Photomicrographs of retinal sections of (A) mock-depleted
(histopathologic score: 1) or (B) NK-depleted
(histopathologic score: 7) mice 5 days after AC inoculation with HSV-1.
Hematoxylin and eosin; original magnification, x70.
|
|
Spread of HSV-1 to the Posterior Segment in NK-Depleted Mice
To determine whether NK cells protect the inoculated eye from
direct spread of HSV-1 to the posterior segment after AC injection,
immunohistochemical staining for HSV-1 was performed on ocular sections
from NK-depleted mice and mock-depleted mice. For these studies, mice
were injected intravenously with anti-asialo GM1
serum on day -1 and injected with 4.0 x
104 PFU of KOS through the AC route on day 0. To
verify the specificity of the anti-HSV-1 antibody, adjacent sections
were incubated with normal rabbit serum and processed identically with
the sections treated with anti-HSV-1 antibody. These control slides
showed no reactivity (not shown). At day 3 pi, HSV-1positive cells
were observed in the choroid in both NK-depleted mice and mock-depleted
mice (not shown). HSV-1positive cells were not observed in the
sensory retina of mice in either group at this time. However, at day 5
pi, HSV-1positive cells were observed in the sensory retina, but not
in the RPE or choroid, of NK-depleted mice (Figs. 4B
4D
). In contrast, HSV-1postive cells were not observed in the
retina, choroid, or RPE of the mock-depleted mice at pi day 5 (Figs. 4A
4C)
.

View larger version (160K):
[in this window]
[in a new window]
|
Figure 4. NK depletion allows virus infection of the ipsilateral retina after AC
inoculation. Photomicrographs of retinal sections from infected,
mock-depleted (A and C), or infected, NK-depleted
(B and D) mice 5 days after inoculation of 4 x 104 PFU of the KOS strain of HSV-1 through the AC route.
Immunohistochemistry was conducted using anti-HSV-1 serum.
Arrows: virus-infected cells in the sensory retina.
Original magnification, x70 (A, C) and x280
(B, D).
|
|
 |
Discussion
|
|---|
After uniocular AC inoculation of the KOS strain of HSV-1 in
BALB/c mice, acute retinal necrosis is observed in the uninoculated
contralateral eye, whereas the retina of the ipsilateral eye is spared
from virus infection and destruction.1
2
3
4
The mechanism
that prevents virus from spreading to the retina of the injected eye
has been puzzling. It is known that this mechanism cannot be
T-cellmediated, because in T-celldepleted mice, virus does not
spread directly from the infected anterior segment to the retina. Even
though bilateral retinitis develops in T-celldepleted mice, retinitis
in the injected eye of T-celldepleted mice results from late (on or
after pi day 9) spread of virus from the suprachiasmatic nucleus
contralateral to the side of inoculation to the optic nerve of the
injected eye and not from direct anterior-to-posterior spread of the
virus.2
4
5
In the normal eye, immune privilege is maintained and
inflammatory damage is prevented by immunosuppressive cytokines, such
as TGF-ß and macrophage migration inhibitory factor, that are
produced within the eye. However, these immunosuppressive ocular
cytokines, which have also been shown to suppress NK
activity,9
10
11
12
13
do not prevent induction of an NK response
after uniocular AC inoculation of the KOS strain of HSV-1. The results
from the studies presented in this article demonstrate that after
uniocular AC inoculation of the KOS strain of HSV-1, there is both a
local (eye and superficial cervical and submandibular lymph nodes) and
a systemic (spleen) NK response, shown by cytolytic activity of
mononuclear cells isolated from these sites against NK-sensitive YAC-1
targets. The reason ocular factors that normally suppress NK activity
do not inhibit NK activation after AC inoculation of HSV-1 may be that
the extensive virus replication and inflammation that occur within 1 to
2 days after AC inoculation1
17
outstrip the eyes
ability to produce these factors.
However, merely determining that AC inoculation of HSV-1 induces
both a local and a systemic NK response does not provide information
about the role of such a response during ocular infection or about how
NK cells limit virus spread in the injected eye. Results from the
immunohistochemistry and histopathologic studies suggest that depletion
of NK cells allowed HSV-1 to spread to the ipsilateral retina early
after infection and that subsequent virus replication in the retina led
to increased retinal damage in NK-depleted mice. Interestingly, virus
was observed at pi day 3 in the choroid, but not in the sensory retina,
in both NK-depleted mice and mock-depleted mice. In both groups of
mice, no virus-infected cells were detected in the choroid or RPE at pi
day 5. However, at pi day 5, the retinas of NK-depleted mice had more
histopathologic changes than the retinas of non-NK-depleted mice, and
the retinal changes were observed coincident with virus infection of
the retina. This observation suggests that after AC inoculation of
HSV-1, the virus is able to spread to the choroid irrespective of the
presence or absence of NK cells. However, NK cells or their products
eliminate HSV-1 from the choroid of normal mice by pi day 5, and in so
doing, protect the retina of the injected eye from virus infection and
destruction.
There is a paucity of information about how NK cells or their products
limit virus spread and replication within the eye. NK cells have been
reported in the anterior segment (iris and corneal limbus) 5 days after
AC inoculation of HSV-1 in BALB/c mice.18
Recently, NK
cells have been shown to modulate retinal destruction in a mouse model
of cytomegalovirus retinitis.19
It is not clear whether
these cells are normally present within the eye and are activated by
virus infection within the ocular compartment, whether these cells are
activated at an extraocular site and migrate to the eye, or whether
there are both ocular and extraocular populations of such cells.
In summary, the results presented in this article support the idea that
NK cells are activated after uniocular AC inoculation of the KOS strain
of HSV-1 and that these cells are important in preventing spread of
this virus from the infected AC to the retina of the inoculated eye.
Additional studies will be required, however, to determine the
mechanism by which such cells prevent virus spread and the origin and
site of activation of these cells.
 |
Footnotes
|
|---|
Supported by Fight for Sight, research division of Prevent Blindness
America Postdoctoral Fellowship PD98015 (MT), and National Institutes
of Health Grant EY06012 (SSA).
Submitted for publication April 20, 1999; revised August 27, 1999; accepted September 9, 1999.
Commercial relationships policy: N.
Corresponding author: Sally S. Atherton, Department of Cellular and
Structural Biology, Mail Code 7762, University of Texas Health Science
Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX
78229-3900. atherton{at}uthscsa.edu
 |
References
|
|---|
-
Whittum, JA, McCulley, JP, Niederkorn, JY, Streilein, JW (1984) Ocular disease induced in mice by anterior chamber inoculation of herpes simplex virus Invest Ophthalmol Vis Sci 25,1065-1073[Abstract/Free Full Text]
-
Whittum, JA, Pepose, JA (1987) Immunologic modulation of virus-induced pathology in a murine model of acute herpetic retinal necrosis Invest Ophthalmol Vis Sci 28,1541-1548[Abstract/Free Full Text]
-
Margolis, TP, LaVail, JH, Setzer, PY, Dawson, CR. (1989) Selective spread of herpes simplex virus in the central nervous system after ocular inoculation J Virol 63,4756-4761[Abstract/Free Full Text]
-
Vann, VR, Atherton, SS (1990) Neural spread of herpes simplex virus after anterior chamber inoculation Invest Ophthalmol Vis Sci 32,2462-2472[Abstract/Free Full Text]
-
Azumi, A, Atherton, SS (1994) Sparing of the ipsilateral retina after anterior chamber inoculation of HSV-1: requirement for either CD4+ or CD8+ T cells Invest Ophthalmol Vis Sci 35,3251-3259[Abstract/Free Full Text]
-
Gumperz, JE, Parham, P. (1995) The enigma of NK cells Nature 378,245-248[Medline][Order article via Infotrieve]
-
Orange, JS, Wang, B, Terhorst, C, Biron, CA (1995) Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration J Exp Med 182,1045-1056[Abstract/Free Full Text]
-
Welsh, RM, Brubaker, JO, VargasCortes, MM, ODonnell, CL (1991) Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infection occur independently of T and B cell function J Exp Med 173,1053-1063[Abstract/Free Full Text]
-
Jampel, HD, Roche, N, Stark, WJ, Roberts, AB (1990) Transforming growth factor-ß in human aqueous humor Curr Eye Res 9,963-969[Medline][Order article via Infotrieve]
-
Cousins, SW, McCabe, MM, Danielpour, D, Streilein, J. (1991) Identification of transforming growth factor-beta as an immunosuppressive factor in aqueous humor Invest Ophthalmol Vis Sci 32,2201-2211[Abstract/Free Full Text]
-
Cousins, SW, Trattler, B, Streilein, JW (1991) Immune privilege and suppression of immunogenic inflammation in the anterior chamber of the eye Curr Eye Res 10,287-297[Medline][Order article via Infotrieve]
-
Apte, RS, Niederkorn, JY (1996) Isolation and characterization of a unique natural killer cell inhibitory factor present in the anterior chamber of the eye J Immunol 156,2667-2673[Abstract]
-
Apte, RS, Sinha, D, Mayhew, E, Wistow, GJ, Niederkorn, JY (1998) Role of macrophage inhibitory factor in inhibiting NK cell activity and preserving immune privilege J Immunol 160,5693-5696[Abstract/Free Full Text]
-
Bukowski, JF, Welsh, RM (1986) The role of natural killer cells and interferon in resistance to acute infection of mice with herpes simplex virus type 1 J Immunol 136,3481-3485[Abstract]
-
RagerZisman, B, Quan, PC, Rosner, M, Moller, JR, Bloom, BR (1987) Role of NK cells in protection of mice against herpes simplex virus-1 infection J Immunol 138,884-888[Abstract]
-
Brandt, CR, Salkowski, CA (1992) Activation of NK cells in mice following corneal infection with herpes simplex virus type-1 Invest Ophthalmol Vis Sci 3,113-120
-
Atherton, SS, Streilein, JW (1987) Two waves of virus following anterior chamber inoculation of HSV-1 Invest Ophthalmol Vis Sci 28,571-579[Abstract/Free Full Text]
-
Young, LH, Foster, CS, Young, JD (1990) In vivo expression of perforin by natural killer cells during a viral infection. Studies on uveitis produced by herpes simplex virus type I Am J Pathol 136,1021-1030[Abstract]
-
Bigger, JE, Thomas, CA, Atherton, SS (1998) NK cell modulation of murine cytomegalovirus retinitis J Immunol 160,5826-5831[Abstract/Free Full Text]
This article has been cited by other articles:

|
 |

|
 |
 
M. Zheng, M. A. Fields, Y. Liu, H. Cathcart, E. Richter, and S. S. Atherton
Neutrophils Protect the Retina of the Injected Eye from Infection after Anterior Chamber Inoculation of HSV-1 in BALB/c Mice
Invest. Ophthalmol. Vis. Sci.,
September 1, 2008;
49(9):
4018 - 4025.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
N. A. Kittan, A. Bergua, S. Haupt, N. Donhauser, P. Schuster, K. Korn, T. Harrer, and B. Schmidt
Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis
J. Immunol.,
September 15, 2007;
179(6):
4219 - 4230.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
E. J. Shillitoe and C. Pellenz
Factors That Limit the Effectiveness of Herpes Simplex Virus Type 1 for Treatment of Oral Cancer in Mice
Clin. Cancer Res.,
April 15, 2005;
11(8):
3109 - 3116.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. J. J. Carr, J. Chodosh, J. Ash, and T. E. Lane
Effect of Anti-CXCL10 Monoclonal Antibody on Herpes Simplex Virus Type 1 Keratitis and Retinal Infection
J. Virol.,
September 15, 2003;
77(18):
10037 - 10046.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
N. M. Archin, L. van den Boom, L. Perelygina, J. M. Hilliard, and S. S. Atherton
Delayed Spread and Reduction in Virus Titer after Anterior Chamber Inoculation of a Recombinant of HSV-1 Expressing IL-16
Invest. Ophthalmol. Vis. Sci.,
July 1, 2003;
44(7):
3066 - 3076.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Zhu, X. Xu, H. Liu, X. Liu, S. Wang, F. Dong, B. Yang, and G. Song
Enhancement of DNA vaccine potency against herpes simplex virus 1 by co-administration of an interleukin-18 expression plasmid as a genetic adjuvant
J. Med. Microbiol.,
March 1, 2003;
52(3):
223 - 228.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. Grubor-Bauk, A. Simmons, G. Mayrhofer, and P. G. Speck
Impaired Clearance of Herpes Simplex Virus Type 1 From Mice Lacking CD1d or NKT Cells Expressing the Semivariant V{alpha}14-J{alpha}281 TCR
J. Immunol.,
February 1, 2003;
170(3):
1430 - 1434.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. B. Pyles, D. Higgins, C. Chalk, A. Zalar, J. Eiden, C. Brown, G. Van Nest, and L. R. Stanberry
Use of Immunostimulatory Sequence-Containing Oligonucleotides as Topical Therapy for Genital Herpes Simplex Virus Type 2 Infection
J. Virol.,
October 11, 2002;
76(22):
11387 - 11396.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. H. Edelmann and C. B. Wilson
Role of CD28/CD80-86 and CD40/CD154 Costimulatory Interactions in Host Defense to Primary Herpes Simplex Virus Infection
J. Virol.,
January 15, 2001;
75(2):
612 - 621.
[Abstract]
[Full Text]
|
 |
|

|
 |

|
 |
 
M. Franchini, C. Abril, C. Schwerdel, C. Ruedl, M. Ackermann, and M. Suter
Protective T-Cell-Based Immunity Induced in Neonatal Mice by a Single Replicative Cycle of Herpes Simplex Virus
J. Virol.,
January 1, 2001;
75(1):
83 - 89.
[Abstract]
[Full Text]
|
 |
|

|
 |

|
 |
 
A. A. Nash
T Cells and the Regulation of Herpes Simplex Virus Latency and Reactivation
J. Exp. Med.,
April 24, 2000;
191(9):
1455 - 1458.
[Full Text]
[PDF]
|
 |
|