Rev. Med. Virol. 2015; 25: 300–319.

Published online 23 July 2015 in Wiley Online Library

(wileyonlinelibrary.com)
Reviews in Medical Virology DOI: 10.1002/rmv.1848

REVIEW
Innate immune response during herpes simplex
virus encephalitis and development of
immunomodulatory strategies
Jocelyne Piret and Guy Boivin*
Research Center in Infectious Diseases, CHU de Québec and Laval University, Quebec City, Quebec, Canada

S U M M A RY
Herpes simplex viruses are large double-stranded DNA viruses. These viruses have the ability to establish a lifelong
latency in sensory ganglia and to invade and replicate in the CNS. Apart from relatively benign mucosal infections,
HSV is responsible for severe illnesses including HSV encephalitis (HSE). HSE is the most common cause of sporadic,
potentially fatal viral encephalitis in Western countries. If left untreated, the mortality rate associated with HSE is ap-
proximately 70%. Despite antiviral therapy, the mortality is still higher than 30%, and almost 60% of surviving individ-
uals develop neurological sequelae. It is suggested that direct virus-related and indirect immune-mediated mechanisms
contribute to the damages occurring in the CNS during HSE. In this manuscript, we describe the innate immune re-
sponse to HSV, the development of HSE in mice knock-out for proteins of the innate immune system as well as
inherited deficiencies in key components of the signaling pathways involved in the production of type I interferon that
could predispose individuals to develop HSE. Finally, we review several immunomodulatory strategies aimed at mod-
ulating the innate immune response at a critical time after infection that were evaluated in mouse models and could be
combined with antiviral therapy to improve the prognosis of HSE. In conclusion, the cerebral innate immune response
that develops during HSE is a “double-edged sword” as it is critical to control viral replication in the brain early after
infection, but, if left uncontrolled, may also result in an exaggerated inflammatory response that could be detrimental to
the host. Copyright © 2015 John Wiley & Sons, Ltd.

INTRODUCTION capacity to invade and replicate in the CNS [1]. A

Herpes simplex viruses are large double-stranded
DNA viruses. Among the key biological properties
of HSV, there are the establishment of a lifelong
latency in dorsal root sensory ganglia and the
*Corresponding author: G. Boivin, FRCP, Centre de recherche en
infectiologie, CHU de Québec, Pavillon CHUL, 2705, Blvd Laurier,
RC-709, Québec (Québec), Canada, G1V 4G2.
E-mail: Guy.Boivin@crchudequebec.ulaval.ca
Abbreviations used
AIM2, absent in melanoma 2; AP-1, activator protein 1; BBB, blood–
brain barrier; CARD, caspase recruitment domain; Casp., caspase;
CCL, C–C motif chemokine ligand; cGAS, cytosolic guanosine-
monophosphate adenosine-monophosphate (cGAMP) synthase; CXCL,
C–X–C motif chemokine ligand; dsDNA, double-stranded DNA;
dsRNA, double-stranded RNA; FADD, Fas-associated death domain;
GFP, green fluorescent protein; HSE, herpes simplex virus encephali-
tis; IFI16, IFN-inducible protein 16; IFNAR, IFN-α/β receptor; IκB,
inhibitor of NF-κB; IKK, IκB kinase; IKKα/β, inhibitor of IκB kinase
α/β; IKKi, inducible IκB kinase; iNOS, inducible nitric oxide synthase;
IPS-1, IFN-β promoter stimulator 1; iPSCs, induced pluripotent stem
cells; IRF, IFN regulatory factor; IRAK, IL-1 receptor-associated ki-
nase; ISGs, IFN-stimulated genes; ISRE, IFN-stimulated response ele-
ment; JAK1, Janus kinase 1; LRR, leucine-rich repeat protein; MAPK,
mitogen-activated protein kinase; Mda5, melanoma differentiation-
associated gene 5; MyD88, myeloid differentiation primary response
US survey from 2005 to 2010 estimated that 53.9%
of adults aged 14–49 years are infected with HSV-
1 and 15.7% with HSV-2 [2]. Transmission of these
viruses is dependent on intimate contacts through
mucosal surfaces. The virus is then transported by
retrograde route via sensory nerves to dorsal root
ganglia where it establishes latency followed by pe-
riodic reactivations and anterograde transport back
to the mucous surfaces [1]. Although HSV-1 is
protein 88; NAP1, NAK-associated protein 1; NEMO, NF-κB essen-
tial modulator; NF-κB, nuclear factor kappa B; NOD, nucleotide-bind-
ing oligomerization domain; NLRs, NOD-like receptors; ODNs,
oligodeoxynucleotides; PI3K, phosphoinositide-3-kinase; PAMPs,
pathogen-associated molecular patterns; PRRs, pathogen recognition
receptors; poly I:C, polyinosinic:polycytidylic acid; RIG-I, retinoic
acid-inducible gene I; RIP, receptor-interacting protein; RLH, RIG-I-
like RNA helicase; ssRNA, single-stranded RNA; STAT, signal trans-
ducer and activator of transcription; STING, stimulator of IFN genes;
TAB, TAK1-binding protein; TAK1, transforming growth factor-β-
activated kinase 1; TANK, TRAF family member-associated NF-κB ac-
tivator; TBK1, TANK-binding kinase 1; TIR, Toll-IL-1 receptor;
TIRAP, TIR-associated protein; TLR, Toll-like receptor; TRAF, TNF
receptor-associated factor; TNFR1, TNF-α receptor 1; TRAM, TRIF-
related adaptor molecule; TRIF, TIR domain-containing adaptor induc-
ing IFN-β; TYK2, tyrosine kinase 2.

Copyright © 2015 John Wiley & Sons, Ltd.

Innate immune response to herpes simplex virus
mainly associated with herpes labialis and HSV-2
with genital herpes, there is a considerable overlap
in viral tropism [2]. Apart from these relatively be-
nign conditions, HSV is also associated with severe
illnesses including ocular infections (keratitis), neo-
natal infections (affecting the skin or disseminated)
and CNS involvement (HSV encephalitis; HSE) [3].
HERPES SIMPLEX VIRUS ENCEPHALITIS
Herpes simplex virus encephalitis is the most com-
mon cause of sporadic fatal viral encephalitis in
Western countries [4]. The incidence of HSE is esti-
mated to be approximately 1 in 250 000 individuals
[5]. Importantly, the mortality rate is in excess of
70% with only 2.5% of all patients returning to nor-
mal function in the absence of antiviral treatment
[6]. The incidence of HSE peaks in childhood
between the age of 6 months to 3 years during
HSV-1 primary infection and thereafter in adults
> 50 years [7]. Virtually all adult cases of HSE are
caused by HSV-1 with about 1/3 of them being
the consequence of primary infection and the re-
maining 2/3 occurring in the presence of pre-
existing antibodies [4].
The pathogenesis of HSE has remained elusive.
Herpes simplex virus encephalitis results in acute
inflammation, congestion and/or hemorrhage,
most prominently in the temporal lobes and usu-
ally asymmetrically [4]. At the microscopic level,
there is diffuse perivascular subarachnoid mono-
nuclear cell infiltrate, gliosis and satellitosis [8]. Al-
though both primary and recurrent HSV infections
can lead to HSE, the route of access of the virus to
the CNS is still controversial. Various animal
models have been developed in an attempt to
mimic the possible routes of infection. Some have
suggested the olfactory and trigeminal nerves as
potential pathways to the CNS with possible estab-
lishment of latency within the brain [9,10]. Intrana-
sal inoculation of HSV-1 to mice produces focal
lesions localized to the temporal lobe(s), similar to
what is observed in humans [11]. It is though that
both direct virus-mediated and indirect immune-
mediated mechanisms play a role in CNS damages,
which may explain why HSE is not more common
among immunocompromised hosts despite recur-
rent mucocutaneous infections. Other lines of evi-
dence that support immune-mediated damages in
animal models of HSE include the predominance
of specific cytotoxic T cells at sites of infection
[12], the correlation between cytokine/nitric oxide
Copyright © 2015 John Wiley & Sons, Ltd.
301
levels and brain injury [13] and the correlation
between infiltration of immune cells in the CNS
and demyelination. It has also been reported that
depletion of macrophages and neutrophils in sus-
ceptible 129 mice enhanced survival whereas resis-
tant immunodeficient B6-E mice transplanted with
bone marrow of 129 mice had accelerated fatal out-
come [14].
The clinical manifestations of HSE include fever,
altered consciousness, abnormal behavior and lo-
calized neurological findings such as seizure and
paralysis [3,15]. Laboratory clues for the diagnosis
include a lymphocytic pleocytosis and a proteinosis
of the CSF, characteristic electroencephalographic
changes and abnormal computed tomographic or
magnetic resonance imaging findings localized to
the temporal lobe(s) [15,16]. PCR detection of
HSV DNA in the CSF has become the diagnostic
method of choice for HSE and has replaced the
more invasive brain biopsy [17,18]. Acyclovir, an
analogue of guanosine, is the antiviral of choice
for the treatment of HSE. At a dosage of
10 mg/kg intravenously every 8 h for 14–21 days,
acyclovir decreases the mortality attributable to
HSE to 30% (instead of 70%) although only 40%
of patients return to normal activities or have mi-
nor impairments [4,15]. A recent international
study suggested that rapid diagnosis and early ad-
ministration of antiviral therapy at the onset of
HSE are keys to a favorable outcome [19].
The topic of this review deals with the cerebral
innate immune response in experimental mouse
models of HSE and the inherited deficiencies in
the immune signaling pathways that may predis-
pose individuals to develop natural HSE. Finally,
we discuss the rational to combine antiviral agents
with immune-based therapy to improve the prog-
nosis of HSE.
INNATE IMMUNE RESPONSE TO HERPES
SIMPLEX VIRUS
Innate immune response constitutes the first line of
host defense that limits viral spread and plays an
important role in the activation of the adaptive
response. Pathogen recognition receptors (PRRs)
recognize conserved microbial molecules known as
pathogen-associated molecular patterns (PAMPs),
to initiate innate immune response and inflammation
(Figure 1) [20–22]. PRRs include Toll-like recep-
tors (TLRs), retinoic acid-inducible gene I (RIG-I)-
like RNA helicases (RLHs), nucleotide-binding
Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
302 J. Piret and G. Boivin

Figure 1. Schematic representation of HSV sensing by pathogen recognition receptors. HSV PAMPS are recognized by host PRRs which
initiate several signaling pathways that activate IRFs, NF-κB and AP-1 transcription factors. This leads to the production of type I IFN and
pro-inflammatory cytokines. Viral glycoproteins are sensed by TLR2 located at the cell surface. The abundant CpG motifs present in the
viral DNA are recognized by endosomal TLR9. In the cytosol, viral dsDNA also induces the synthesis of cGAMP by cGAS which activates
the STING/TBK1 pathway. Intermediate dsRNA produced during the viral replication are recognized by endosomal TLR3 and cytosolic
RIG-I and Mda5 sensors. During the second wave of type I IFN production, IFN-α/β bind to the IFNAR receptor, the signal is transduced
to JAK1 and TYK2 that respectively phosphorylate STAT1 and STAT2. The complex of phosphorylated STAT1 and STAT2
heterodimerizes with IRF9 and translocates to the nucleus to encode antiviral effectors that establish an antiviral state in the infected cells
as well as in the neighboring non-infected cells

oligomerization domain (NOD)-like receptors (NLRs)
as well as cytosolic DNA sensors.
TLRs are mainly expressed at the cell surface except
TLRs 3, 7, 8 and 9 that are localized in the endosomes.
The chaperone protein Unc93B is essential for the
translocation of TLRs 3, 7 and 9 from the endoplasmic
reticulum to the endosomes [23]. The PAMPs recogni-
tion by TLRs induces the recruitment of adaptor pro-
teins containing a Toll/IL-1 receptor (TIR) domain
including myeloid differentiation primary response
protein 88 (MyD88), TIR-associated protein (TIRAP),
TIR-domain-containing adaptor inducing IFN-β
(TRIF) and TRIF-related adaptor molecule (TRAM)
[20,22]. According to the adaptor and to the TLR,
the MyD88-dependent (TLRs 1, 2, 4, 5, 6, 7, 8 and
9) and/or the TRIF-dependent (TLRs 3 and 4)
pathway(s) can be activated to induce appropriate
immune response to pathogens. Recognition of
HSV is mediated by TLRs 2, 3 and 9 (Figure 1)
[24–26]. HSV particles are first sensed by TLR2
localized at the cell surface through the detection
of viral glycoproteins [27,28]. After entry, viral
genomic DNA, which contains abundant unme-
thylated CpG motifs, is detected by endosomal
TLR9 [29–31]. In recent years, the implication of
cyclic guanosine monophosphate-adenosine mo-
nophosphate (cGAMP) synthase (cGAS) in the
recognition of cytosolic HSV dsDNA has been
described [32]. cGAS is activated by dsDNA and
catalyzes the synthesis of a noncanonical cyclic
dinucleotide from ATP and GTP. cGAMP is an
endogenous second messenger that binds to and

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus
activates the adaptor protein stimulator of IFN
genes (STING) [33,34]. It is suggested that other
cytosolic dsDNA sensors, such as absent in mela-
noma 2 (AIM2), interferon-inducible protein 16
(IFI16) and RNA polymerase III, may also contrib-
ute to the innate immune response to HSV [35].
Replication of the viral genome leads to accumula-
tion of intermediate dsRNAs which are then sensed
by endosomal TLR3 [36]. RLHs consist of a group
of RNA helicases, namely RIG-I and melanoma
differentiation-associated gene 5 (Mda5), that are
involved in the recognition of viral RNA in the cy-
toplasm [20]. RIG-I recognizes short dsRNA struc-
tures and 5′-triphosphate ssRNA whereas Mda5
senses long dsRNA that has higher order structures
[37]. As TLRs, RLHs interact with adaptor proteins
to recruit downstream effectors [20]. RIG-I and
Mda5 recognize replication intermediate dsRNA
structures of HSV and interact with IFN-β promoter
stimulator-1 (IPS-1) adaptor [38–40]. Viral com-
ponents sensed by these specific PRRs trigger
activation of the transcription of nuclear factor-κB
(NF-κB), activator protein 1 (AP-1) and IFN
regulatory factor (IRF) family members. These
transcription factors regulate the expression of
chemokines, pro-inflammatory cytokines and type
I IFNs [24–26] which consist of a single IFN-β and
more than a dozen IFN-α subtypes [41]. Proteins
of the IRF family, in particular IRF3 and IRF7,
tightly control the transcription of IFN-α/β genes
[42] and are strong inducers of type I IFNs [22].
During initial induction of type I IFNs, IRF3 and
NF-κB, which are constitutively expressed, are
respectively phosphorylated by TANK-binding
kinase 1 (TBK1) and IκB kinase (IKK) complex
[43,44]. Once activated, they translocate to the nu-
cleus, where they bind to the IFN promoter to form
the IFN enhanceosome [45]. In concert with IRF3,
IRF7 amplifies and facilitates the expression of the
type I IFN cascade [46]. Phosphorylated IRF7 can
form a homodimer or a heterodimer with IRF3 to
induce differential effects on the expression of type
I IFN gene family members [47].
The initial type I IFNs produced act in both auto-
crine and paracrine manners through the IFN-α/β
receptor (IFNAR) composed of the IFNAR1 and
IFNAR2 subunits, which activates components of
the Janus kinase-signal transducer and activator of
transcription (JAK/STAT) signaling pathway [48].
STAT1 interacts with STAT2 and IRF9 to form a
complex that binds to the IFN-stimulated response
Copyright © 2015 John Wiley & Sons, Ltd.
303
element (ISRE) promoter regions and stimulates
type I IFN-depending gene transcription, including
IRF7 [49,50]. This cascade also results in the induc-
tion of the expression of IFN-stimulated genes
(ISGs) encoding antiviral effectors important to
limit viral spread and to establish an antiviral state
in the infected cells as well as in the neighboring
non-infected cells [51].
CEREBRAL INNATE IMMUNE RESPONSE TO
HERPES SIMPLEX VIRUS ENCEPHALITIS
Microglial cells are the first line of immune defense
in the brain parenchyma [52]. They can be activated
during systemic infection without loss of integrity
of the blood–brain barrier (BBB). The circum-
ventricular organs and the choroid plexus are stra-
tegically positioned to detect PAMPs in the blood.
This leads to the progressive activation of resident
microglial cells and to the production of TNF-α,
which acts in autocrine and paracrine manners to
activate the immune cells across the brain paren-
chyma [53]. Similar to macrophages, parenchymal
microglial cells express TLRs, respond to PAMPs
and produce pro-inflammatory mediators. In nor-
mal conditions, the trafficking of leukocytes from
the blood to the CNS is exquisitely controlled by
the BBB [54]. The activation of innate immune re-
sponse in resident microglial cells following an
infection induces a marked recruitment, prolifera-
tion and activation of microglial cell precursors
from the blood to affected regions of the brain
[55]. Stimulated astrocytes can also induce the
expression of pro-inflammatory cytokines and
chemokines that can initiate leukocytes migration
across the BBB [56]. By using chimeric mice with
bone marrow-derived cells expressing the green
fluorescent protein (GFP), our group demonstrated
a recruitment of GFP positive cells into the CNS af-
ter intranasal infection with HSV-1 [57]. These infil-
trating cells originating from the periphery could
contribute to the cerebral innate immune response
to the virus.
The expression of TLR2, TLR3 and TLR9 was
strongly up-regulated and widely distributed
throughout the brain of mice infected by the intra-
nasal route with HSV-1 whereas the other TLRs
were barely detected in some regions or almost un-
detectable [58]. More specifically, TLR2 and TLR9
are expressed by microglia and astrocytes whereas
TLR3 is present in microglia, astrocytes, oligoden-
drocytes and neurons [59]. In vitro studies have
Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
304
demonstrated that cytosolic RIG-I and Mda5 sen-
sors are found in microglia, astrocytes and neurons
[60,61]. The adaptor protein STING has been de-
tected in microglial cells and astrocytes [62]. Thus,
both hematopoietic and non-hematopoietic resi-
dent cells of the CNS have been reported to partic-
ipate to the innate immune response to HSV.
HERPES SIMPLEX VIRUS ENCEPHALITIS IN
KNOCK-OUT MOUSE MODELS
Different mouse strains (in a C57BL/6 or
C57BL/6x129 genetic background) knock-out for
PRRs, adaptor proteins, mediators of inflammation
and their receptors have been used to evaluate the
specific role of several components of the innate
immune response to HSV in the CNS (Table 1).
Intranasal infection of mice deficient for TLR2
with HSV-1 had no effect on survival rate and viral
titers in the brain compared to wild-type controls
[63,64]. Other groups reported that intracranial or
intraperitoneal inoculation of HSV-1 to mice lack-
ing TLR2 increased the survival rates but did not
affect the viral titers in the brain [65,66]. The latter
mice responded to HSV-1 infection with an im-
paired immune response [65]. Similarly, intraperi-
toneal inoculation of HSV-2 to TLR2-deficient
mice did not affect the viral titers in the brain com-
pared to wild-type [67]. These data suggest that the
inflammatory response mediated by TLR2 in the
CNS could be detrimental to the host. Mice lacking
TLR9 infected intranasally with HSV-1 had in-
creased mortality rates because of uncontrolled vi-
ral replication and increased levels of chemokines
in the brain but the mortality rate was lower than
in mice deficient for both TLR2 and TLR9 [64]. Mice
deficient for TLR9 infected with HSV-1 by the intra-
cranial route or with HSV-2 by the intraperitoneal
route had no increased susceptibility to infection
[66,67]. These data suggest that TLR9 does not ex-
ert a strong effect in the innate immune defense
against HSV infection. The potential cooperative
action of TLR2 and TLR9 in the recognition of
HSV in the CNS has been investigated by several
groups. Mice lacking both TLR2 and TLR9 infected
intranasally with HSV-1 had increased mortality
rates because of uncontrolled viral replication,
higher levels of chemokines and lower production
of IL-1β and IFN-γ in the brain compared to wild-
type and TLR2- or TLR9-deficient mice [64]. In con-
trast, inoculation of HSV-1 by the intracranial route
had no effect on survival rate and viral titers in the
Copyright © 2015 John Wiley & Sons, Ltd.
J. Piret and G. Boivin
brain [66]. TLR2 and TLR9 double knock-out mice
were also more susceptible to viral dissemination
to the CNS than either TLR2- or TLR9-deficient
mice after intraperitoneal or vaginal inoculation of
HSV-2 [67]. It was thus proposed that both TLR2
and TLR9 recognize HSV components and act in
an additive manner on the activation of the adaptor
protein MyD88 to initiate an immune response. In
this respect, intranasal infection with HSV-1 to mice
deficient for MyD88 resulted in an increased
mortality rate because of an uncontrolled viral
replication in the brain compared to wild-type [63].
The viral dissemination to the CNS was also increased
in mice lacking MyD88 inoculated with HSV-2 by
the intraperitoneal and vaginal routes [67,68].
Sensing of HSV dsRNA is mediated by
endosomal TLR3 and cytoplasmic RIG-I and
Mda5 which signal through TRIF and IPS-1 adap-
tor proteins, respectively [36,38–40]. The relative in-
fluence of these sensors following HSV-1 infection
has been investigated by our group in TRIF- and
IPS-1-deficient mice [69]. The brain viral load and
the mortality rate were markedly increased in
TRIF- and IPS-1-deficient mice compared to wild-
type controls following intranasal infection with
HSV-1. Moreover, the production of IFN-β was sig-
nificantly reduced at a critical time during the in-
fection and could explain the higher susceptibility
of both deficient mice. This study suggests that
both endosomal TLR3 and cytoplasmic helicase
sensors are implicated in the signaling pathways
leading to IFN-β production during HSE with the
TLR3-TRIF pathway being predominant over
RIG-I/Mda5-IPS-1 pathways. TLR3-deficient mice
were highly susceptible to HSV-2 dissemination to
the CNS after vaginal infection [70]. The viral tro-
pism was extended to astrocytes that became per-
missive to the infection. It was thus suggested
that TLR3 expressed by astrocytes senses HSV-2 af-
ter entry into the CNS and limits the spread of the
virus to neurons.
The deficiency of Unc93B, involved in endo-
somal TLR3, TLR7 and TLR9 sorting, decreased
the survival rate but did not affect viral replication
or type I IFN levels in the brain of mice infected
with HSV-1 by the intracranial route [66].
More recently, it was also reported that mice
lacking cGAS or STING, involved in the recogni-
tion of cytosolic HSV dsDNA, infected intrave-
nously with HSV-1 exhibited enhanced HSV titers
in the brain, decreased levels of IFN-α/β in serum
Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus 305

Table 1. Outcome of herpes simplex virus encephalitis in knock-out mouse models

Route of
inoculation Observations in
Viral strain Mouse genetic deficient mice
Deficiency Inoculum background compared to wild-type References

Pathogen recognition receptors

TLR2 HSV-1 EK Intranasal No effect on survival rate [63,64]
104/106 PFU C57BL/6 No effect on viral titers in the brain
HSV-1 7134R Intracranial Increased survival rate [66]
3 × 104 PFU C57BL/6 No effect on viral titers in
the brain
No effect on IFN-β levels in
the brain
HSV-1 KOS Intraperitoneal Increased survival rate [65]
109 PFU C57BL/6x129 No effect on viral titers in
the brain
Decrease in CCL2 levels in
the brain
Less brain inflammation by
histopathology
HSV-2 MS Intraperitoneal No effect on viral titers in the brain [67]
106 PFU C57BL/6
TLR3 HSV-2 333 Vaginal More susceptible to clinical [70]
disease in the CNS
6.7 × 104 PFU C57BL/6 Increase in viral titers in the
cerebellum
No effect on type I IFN and
TNF-α levels in the brain
Broader tropism to astrocytes
TLR9 HSV-1 EK Intranasal Increased mortality rates [64]
106 PFU C57BL/6 Increase in viral titers in the brain
Increase in CCL2 and CXCL10
levels in the brain
HSV-1 7134R Intracranial No effect on survival rate [66]
3 × 104 PFU C57BL/6 No effect on viral titers in the brain
No effect on IFN-β levels in
the brain
HSV-2 MS Intraperitoneal No effect on viral titers in the brain [67]
106 PFU C57BL/6
TLR2/TLR9 HSV-1 EK Intranasal Increased mortality rate [64]
106 PFU C57BL/6 Increase in viral titers in
the brain
Decrease in IL-1β and IFN-γ
levels in the brain
Increase in CCL2 and CXCL10
levels in the brain

(Continues)

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
306 J. Piret and G. Boivin

Table 1.
0. (Continued)
Route of
inoculation Observations in
Viral strain Mouse genetic deficient mice
Deficiency Inoculum background compared to wild-type References

HSV-1 7134R Intracranial No effect on survival rate [66]

3 × 104 PFU C57BL/6 No effect on viral titers in the brain
No effect on IFN-β levels in
the brain
HSV-2 MS Intraperitoneal Increased susceptibility to infection [67]
106 PFU C57BL/6 Increase in viral titers in the brain
HSV-2 333 Vaginal Increased mortality rate [67]
6.7 × 104 PFU C57BL/6 Increase in viral titers in
the brain stem
Decrease in TNF-α and
CXCL9 levels in the brain
cGAS HSV-1 aka KOS Intravenous Increased mortality rate [32]
106 PFU C57BL/6 Increase in viral titers in
the brain
Decrease in IFN-α/β
production in serum
TLRs 3, 7, 9 routing
Unc93B HSV-1 7134R Intracranial Increased mortality rate [66]
3 × 104 PFU C57BL/6 No effect on viral
replication in the brain
No effect on IFN-β levels
in the brain
Adaptor proteins
MyD88 HSV-1 EK Intranasal Increased mortality rate [63]
104 PFU C57BL/6 Increase in viral titers in the brain
Increased inflammation in
the brain by histopathology
HSV-2 MS Intraperitoneal Increase in viral titers in the brain [67]
106 PFU C57BL/6
HSV-2 333 Vaginal Increased mortality rate [68]
9 × 104 and 9 × 103 C57BL/6
PFU
TRIF HSV-1 H25 Intranasal Increased mortality rate [69]
7.5 × 105 PFU C57BL/6 Increase in the brain viral load
Decrease in IFN-β production
in the brain
IPS-1 HSV-1 H25 Intranasal Increased mortality rate [69]
7.5 × 105 PFU C57BL/6 Increase in the brain viral load
Decrease in IFN-β production
in the brain

(Continues)

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus 307

Table 1.
0. (Continued)
Route of
inoculation Observations in
Viral strain Mouse genetic deficient mice
Deficiency Inoculum background compared to wild-type References

STING HSV-1 KOS Intravenous Increased mortality rate [71]

107 PFU Increase in viral titers in
the brain
Decrease in IFN-α/β
production in serum
Receptors of IFN-α/β and TNF-α
IFNAR HSV-1 7134R Intracranial Increased mortality rate [66]
3 × 104 PFU C57BL/6 Increase in viral titers in
the brain
Increase in IFN-β production
in the brain
HSV-2 333 Vaginal More susceptible to clinical [70]
6.7 × 104 PFU C57BL/6 disease in the CNS
No effect on viral titers
in the cerebellum
No effect on type I IFN
and TNF-α levels in the brain
Broader tropism to astrocytes
TNFR1 HSV-1 EK Intracranial Increased mortality rate [72]
102 PFU C57BL/6 Increase in viral titers in the brain
Decrease in CCL3 and CCL5
levels in the brain
Pro-inflammatory cytokines
IL-1β HSV-1 H25 Intranasal Increased mortality rate [73]
3 × 106 PFU C57BL/6 Increase in the brain viral load
Decrease in the expression of
TLR2 in the brain
Decrease in CCL2, IL-12,
IFN-β and IFN-γ levels in the brain
TNF-α HSV-1 H25 Intranasal Increased mortality rate [73]
3 × 106 PFU C57BL/6 Increase in the brain viral load
Decrease in the expression of
TLR2 in the brain
Decrease in CCL2, IL-12,
IFN-β and IFN-γ levels in the brain

and reduced survival rates compared to wild-type
controls [32,71].
Type I IFN is crucial for the survival of mice in-
fected by direct intracranial inoculation as mice lack-
ing the type I IFN receptor died rapidly from the
infection and demonstrated increased titers of HSV
in the brain [66]. IFNAR-deficient mice infected vagi-
nally with HSV-2 failed to induce the expression of
most PRRs (eg., TLR2, TLR3, RIG-I and Mda5) in
the brain which could explain the more severe disease

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
308
and the increased mortality seen in these animals [70].
The deficiency of the TNF-α receptor 1 (TNFR1) also
resulted in an increased mortality rate because of an
uncontrolled viral replication in the brain [72]. The
survival rate was decreased in mice deficient for
IL-1β and/or TNF-α compared to the wild-type
following intranasal infection with HSV-1 because of
an uncontrolled viral replication, a reduced expres-
sion of TLR2 and a decrease in the production of
cytokines/chemokines in the CNS [73].
Overall, these data suggest that the inability to
rapidly generate an adequate innate immune re-
sponse to the virus could ultimately lead to a loss
of viral containment.
INHERITED DEFICIENCIES OF THE INNATE
IMMUNE SYSTEM IN HUMAN CASES OF
HERPES SIMPLEX VIRUS ENCEPHALITIS
Most genetic predispositions to HSE in humans re-
sult from deficiencies in the type I IFN production
pathways (Table 2). The first report was the
discovery of homozygous autosomal recessive
complete mutations in the Unc93B1 gene in two un-
related consanguineous children suffering from re-
current episodes of HSE [74]. Mutations (i.e.
1034del4/G781A) led to a premature termination
codon and a complete loss-of-expression of the pro-
tein. Dermal fibroblasts, which selectively express
TLR3, derived from these patients were stimulated
with polyinosinic:polycytidylic acid (poly I:C; a
synthetic form of dsRNA) and HSV-1 and demon-
strated an impaired IFN-β and -λ response com-
pared to those of controls. Patients’ fibroblasts
were more permissive to HSV-1 infection, which re-
sulted in an increased viral replication and cell
death compared to controls. Pre-treatment of cells
with exogenous IFN-α2b before viral infection re-
stored viral titers and cell viability to control levels.
These data suggested that a production of type I
IFN dependent of Unc93B and TLR3 is involved
in the protective immunity against HSE. The pro-
duction of IFN-α/β and -λ in PBMCs derived from
Unc93B-deficient patients was abolished in re-
sponse to agonists of TLRs 7, 8 and 9. Despite this
deficiency, these patients were normally resistant
to other infectious diseases including viral infec-
tions suggesting that the responses of TLRs 7, 8
and 9 could be redundant for the production of
IFN-α/β and -λ outside the CNS.
A heterozygous autosomal dominant negative
mutation was subsequently identified in the TLR3
Copyright © 2015 John Wiley & Sons, Ltd.
J. Piret and G. Boivin
gene of two unrelated children with HSE from
nonconsanguineous families [75]. The mutation
(P554S), located in the ectodomain of TLR3, re-
sulted in a loss-of-function of the protein. The case
of another child suffering from HSE and who car-
ried a heterozygous autosomal recessive complete
mutation in the TLR3 gene was then described
[76]. One allele harbored the amino acid substitu-
tion P554S and the other allele had a stop codon
resulting in the premature termination and a loss-
of-function of the protein. The production of IFN-
β and -λ was reduced but not abolished in the fibro-
blasts of the first two patients after stimulation
with poly I:C and HSV-1 whereas it was completely
abolished in fibroblasts of the other one. All pa-
tients’ fibroblasts were more permissive to infection
with HSV-1. Viral replication and cell viability
could be restored to control levels by pre-treatment
of cells with recombinant IFN-α2b before infection.
In contrast, PBMCs from all patients responded
normally to poly I:C and HSV-1 activation. Re-
cently, two other patients carrying heterozygous
mutations (G743D+R811I and L360P) in the TLR3
gene that resulted in a loss-of-function respectively
because of a lower expression or a lack of cleavage
of the protein as well as a single patient with a ho-
mozygous hypomorphic mutation (R867Q) were
described [77]. Dermal fibroblasts derived from
these three patients had severely impaired response
to stimulation with poly I:C and HSV-1 as well as
an increased susceptibility to HSV-1 infection. All
patients with deficiency in TLR3 were normally re-
sistant to other infectious diseases including viral
infections. Four of the six children carrying TLR3
deficiency (i.e. one child with P554S mutation and
patients with G743D/R811I, L360P and R867Q mu-
tations) as well as the two children with autosomal
recessive Unc93B deficiency presented HSE re-
lapses (Table 2) suggesting that recurrences could
be more frequent in individuals with inborn errors
of TLR3 immunity [77].
The importance of the TLR3-dependent signaling
pathway in the protective immunity against HSE
was confirmed by the identification of a series of
deficiencies in proteins involved in this axis. A het-
erozygous autosomal negative dominant mutation
in the TRAF3 gene was discovered in one child suf-
fering from HSE and no other unusually severe in-
fectious diseases, especially of viral origin [78]. The
mutation (R118W) was associated with a reduced
stability of the protein. The production of IFN-β
Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus 309

Table 2. Genetic predispositions to herpes simplex virus encephalitis in humans

Mutated gene/protein No. of identified patients
Mutation characteristics Susceptibility to infections Immunological findings References

TLR3-dependent pathway deficiency

Unc93B1/Unc93B Two children with Loss-of-expression [74]
1034del4 and G781A recurrent HSE Impaired IFN-β and -λ in
Homozygous Normal resistance to other fibroblasts in response to
Autosomal recessive infectious diseases poly I:C and HSV-1
complete including viral infections Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
Impaired IFN-α/β and -λ
in PBMCs in response to
agonists of TLRs 7, 8 and 9
TLR3/TLR3 Two children with HSE Loss-of-function [75]
P554S One of the two children Partial defect in IFN-β and
Heterozygous had recurrences -λ in fibroblasts in
Autosomal dominant Normal resistance to other response to poly I:C
negative infectious diseases and HSV-1
including viral infections Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
Normal response to poly
I:C in PBMCs
TLR3/TLR3 One child with HSE Premature termination, [76]
P554S and E746stop Normal resistance to other loss-of-function
Heterozygous infectious diseases Abolition of IFN-β and -λ
Autosomal recessive including viral infections in fibroblasts in response
complete to poly I:C and HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
Normal response to poly
I:C or HSV-1 in PBMCs
TLR3/TLR3 One child with recurrent Loss-of-expression, loss- [77]
G743D and R811I HSE of-function
Heterozygous Normal resistance to other IFN-β and -λ responses
Autosomal dominant infectious diseases including almost abolished in
partial viral infections fibroblasts stimulated
Haploinsufficiency with poly I:C and HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
(Continues)

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
310 J. Piret and G. Boivin

Table 2.
. (Continued)
(Continued)
Mutated gene/protein No. of identified patients
Mutation characteristics Susceptibility to infections Immunological findings References

TLR3/TLR3 One child with recurrent Lack of cleavage, loss-of-

L360P HSE function [77]
Heterozygous Normal resistance to other Severely impaired IFN-β
Autosomal dominant infectious diseases and -λ responses in
negative, partial including viral infections fibroblasts stimulated
with poly I:C and HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
TLR3/TLR3 One child with HSE Loss-of-function [77]
R867Q followed by HSE relapse Severely impaired IFN-β
Homozygous Normal resistance to other and -λ responses in
Autosomal recessive infectious diseases fibroblasts stimulated
partial including viral infections with poly I:C and HSV-1
Hypomorphic Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
TRAF3/TRAF3 One child with HSE Loss-of-expression, loss- [78]
R118W Normal resistance to other of-function
Heterozygous infectious diseases Impaired IFN-β and -λ
Autosomal dominant including viral responses in fibroblasts
negative, partial infections stimulated with poly I:C
and HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
TRIF/TRIF One child with HSE Loss-of-expression, loss- [80]
R141stop Normal resistance to other of-function
Homozygous infectious diseases Abolition of IFN-β and -λ
Autosomal recessive including viral infections in fibroblasts in response
complete to poly I:C and HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b
TRIF/TRIF One out of 3 children Not a complete loss-of- [80]
S186L with HSE function
Heterozygous Impaired IFN-β and -λ in
fibroblasts in response to
poly I:C and HSV-1

(Continues)

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus 311

Table 2.
. (Continued)
(Continued)
Mutated gene/protein No. of identified patients
Mutation characteristics Susceptibility to infections Immunological findings References

Autosomal dominant Fibroblasts more

negative, partial permissive to HSV-1
Hypomorphic Rescue with exogenous
IFN-α2b

TBK1/TBK1 One child with HSE Loss-of-function [81]

G159A Normal resistance to other Severely impaired
infectious diseases IFN-β and -λ in
Heterozygous including viral infections fibroblasts in response
Autosomal dominant to poly I:C
negative, partial Impaired IFN-β and -λ in
fibroblasts in
response to HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b

TBK1/TBK1 One child with HSE Loss-of-expression, loss- [81]

D50A Normal resistance to other of-function
Heterozygous infectious diseases Normal IFN-β and -λ in
Autosomal dominant including viral infections fibroblasts in
partial response to poly I:C
Haploinsufficiency Impaired IFN-β and -λ in
fibroblasts in
response to HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b

Canonical IKK complex regulation deficiency

IKBKG/NEMO One child with lethal HSE
110-111insC Susceptibility to infections
X-linked recessive by pyogenic bacteria,
Hypomorphic mycobacteria and to a
lesser extent viruses
and fungi
Expression of a truncated [84]
protein
Impaired IFN-β and -λ in
fibroblasts in response to
poly I:C and HSV-1
Fibroblasts more
permissive to HSV-1
Rescue with exogenous
IFN-α2b

(Continues)

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
312 J. Piret and G. Boivin

Table 2.
. (Continued)
(Continued)
Mutated gene/protein No. of identified patients
Mutation characteristics Susceptibility to infections Immunological findings References

Type 1 IFN response deficiency

STAT1/STAT1 One child with recurrent
1757-1758delAG HSE; lethal
Homozygous Severe mycobacterial and
Autosomal recessive viral diseases
complete
Classical MyD88-dependent pathway deficiency
MyD88/MyD88 26 patients
Autosomal recessive No increase susceptibility to
HSE
Susceptibility to infections by
pyogenic bacteria and normal
resistance to fungi, parasites,
viruses and many bacteria
IRAK-4/IRAK-4 52 patients
Autosomal recessive No increase susceptibility to
HSE
Susceptibility to infections
by pyogenic bacteria and
normal resistance to
fungi, parasites, viruses
and many bacteria
Loss-of-expression, loss- [90]
of-function
Response of fibroblasts to
IFN-α/β impaired
IFN-α2b had no effect on
HSV replication in
fibroblasts
No IL-6 production by
whole blood cells after [89,93]
activation with IL-1 or
agonists of TLRs 7, 8 and 9
Normal responses to
TLR3 agonist
No IFN-α/β and -λ
production by whole [89,94]
blood cells and fibroblasts
after activation with IL-1
or agonists of TLRs 7, 8
and 9
Normal responses to
TLR3 agonist

and -λ was impaired in the patient’s fibroblasts
stimulated with poly I:C and HSV-1 and resulted
in an increased viral replication and cell death that
could be rescued by pre-treatment with exogenous
IFN-α2b. Apart from TLR3, the TRAF3 protein acts
downstream from other receptors inducing the pro-
duction of type I and III IFNs as well as the TNF re-
ceptor [79]. Therefore, the cellular response was
also impaired following specific stimulation of
these pathways. The TRAF3-deficient patient was
susceptible to HSE only suggesting that impair-
ment of TLR3-dependent induction of IFNs in the
CNS could be involved. Two other children with
HSE who harbored mutations in the TRIF gene
coding for the TRIF adaptor protein of TLR3 were
described [80]. The first patient carried a homozy-
gous autosomal recessive complete mutation
(R141stop) that led to a loss-of-expression of the
protein whereas the other one had a heterozygous
autosomal dominant mutation (S186L) that re-
sulted in an altered protein activity. The production
of IFN-β and -λ in response to activation with poly
I:C and HSV-1 was respectively abolished or im-
paired in fibroblasts of the first and the second pa-
tient. Fibroblasts of both patients were more
permissive to HSV-1 infection and could be rescued
by pre-treatment with exogenous IFN-α2b. Finally,
mutations in the TBK1 gene were identified in
two children [81]. TBK1 is a kinase at the crossroad
of signaling pathways leading to the production of
type I IFN such as TLR3 and sensors of cytosolic
dsRNA and dsDNA [82]. The first patient had a
heterozygous autosomal dominant negative muta-
tion (G159A) that resulted in a loss-of-function of
the kinase activity. The IFN-β and -λ responses
were severely impaired in patient’s fibroblasts

Copyright © 2015 John Wiley & Sons, Ltd. Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus
stimulated with poly I:C and HSV-1. The second
patient carried a heterozygous autosomal domi-
nant mutation (D50A) that led to a decrease in the
expression and stability of the protein. The re-
sponse of patient’s fibroblasts to activation with
poly I:C was normal whereas it was impaired fol-
lowing stimulation with HSV-1.
Children with inborn errors in TLR3 immunity
suffering from HSE are not susceptible to other vi-
ral infections suggesting that TLR3-independent
IFN responses to other viral components may con-
fer protection against a wide range of viruses in
these patients. Moreover, these children are not
prone to HSV-1 infections outside the CNS. Thus,
in humans, TLR3 could play a non-redundant role
in the CNS for protection against HSV-1 during pri-
mary infection but could be otherwise largely re-
dundant in host defense [75,76]. It was suggested
that the restricted susceptibility to HSE seems to re-
sult from impaired TLR3-dependent type I IFN
production by non-hematopoietic cells of the CNS
infected with HSV-1 and that TLR3-independent
or residual TLR3-dependent signaling outside the
CNS may contribute to antiviral immunity. To
strengthen this hypothesis, induced pluripotent
stem cells (iPSCs) derived from patients deficient
for Unc93B and TLR3 were differentiated into neu-
rons, astrocytes and oligodendrocytes [83]. Neu-
rons and oligodendrocytes were more susceptible
to HSV-1 infection compared to differentiated con-
trol iPSCs and viral infection could be rescued by
a pre-treatment with exogenous IFN-α or IFN-β indi-
cating that non-hematopoietic cells of the CNS could
be involved in the protective immunity against HSE.
It is thus suggested that non-hematopoietic intrinsic
immunity could play a role in the protection against
HSV-1 primary infection of the CNS beyond innate
and adaptive hematopoietic immunity.
A mutation in the IKBKG gene coding for the NF-
κB essential modulator (NEMO) protein was
identified in a child who died from HSE [84].
NEMO is a regulatory subunit of the IKK complex
activating the canonical NF-κB signaling pathway
which acts downstream of multiple receptors [85].
The X-linked recessive mutation (110-111insC) was
hypomorphic and resulted in the expression of a
truncated protein. Both fibroblasts and PBMCs iso-
lated from this patient had impaired IFN-β and -λ
production in response to poly I:C and HSV-1 acti-
vation. This deficiency is mostly associated with an
increased susceptibility to infections caused by
Copyright © 2015 John Wiley & Sons, Ltd.
313
pyogenic bacteria, mycobacteria and to a lesser ex-
tent viruses and fungi [86–89]. However, patients
carrying NEMO mutations could potentially be
more vulnerable to HSE.
Mutations in the STAT1 gene were identified in
several patients and were mostly associated with
an increased susceptibility to mycobacterial and viral
diseases [90–92]. However, one of these patients died
from disseminated HSV-1 infection with recurrent
HSE [90]. This child carried a homozygous autoso-
mal recessive complete mutation (1757–1758delAG)
that resulted in a loss-of-expression and loss-of-
function of the protein and the abolition of IFN-α/β
and -λ cellular response to poly I:C and HSV-1 stim-
ulations. Pre-treatment of patient’s fibroblasts with
exogenous IFN-α2b had no effect on HSV-1 replica-
tion. Because of the important role of STAT1 in the
type I IFN response, it is suggested that its defi-
ciency could predispose individuals to multiple vi-
ral infections, including HSE.
Deficiencies in the MyD88 adaptor protein and
its associated cytosolic IL-1 receptor-associated ki-
nase 4 (IRAK-4) were identified in several patients
with increased susceptibility to infections caused
by pyogenic bacteria and normal resistance to
fungi, parasites, many bacteria and viruses includ-
ing HSV-1 [89]. The production of IL-6 was im-
paired in whole blood cells from MyD88-deficient
patients after activation with IL-1 or agonists of
TLRs 7, 8 and 9 but not following stimulation with
agonists of TLR3 [93]. Whole blood cells and fibro-
blasts of IRAK-4-deficient patients did not produce
IFN-α/β and -λ in response to IL-1 and agonists of
TLRs 7, 8 and 9 but the response to TLR3 agonist
was normal [94]. These data suggest that the classi-
cal MyD88-dependent pathway is redundant in the
protective immunity against HSE and reinforce the
notion that the TLR3-dependent pathway is pre-
dominant in that context.
IMMUNOMODULATORY STRATEGIES
AGAINST HERPES SIMPLEX VIRUS
ENCEPHALITIS
The cerebral innate immune response that develops
during HSE is a «double-edged sword» as it is crit-
ical to control HSV replication in the brain early af-
ter infection but, if uncontrolled, may also result in
an exaggerated inflammatory response that could
be detrimental to the host. Thus, the host innate im-
mune response must be finely balanced to suppress
viral replication and cell death while limiting
Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
314
inflammation in a sensitive tissue such as the brain
(Figure 2). Immunomodulatory strategies aimed at
blocking the innate immune response at a critical
time after infection may thus have beneficial effects
by controlling the late onset excessive inflamma-
tion of the CNS that develops during HSE. Such
immunomodulatory strategies could be eventually
combined with specific antiviral therapy.
The mechanism of action of glucocorticoids, which
are broad-spectrum anti-inflammatory agents, im-
plies the promotion of anti-inflammatory monocytes
which seem to be actively involved in the resolution
of immune reactions [95,96]. Several human case re-
ports and series have indicated a clinical improve-
ment in patients suffering from HSE treated with
corticosteroids combined with acyclovir [97–100]. A
retrospective analysis of a larger number of patients
with HSE showed that administration of adjunctive
glucocorticoids was an independent predictor of a
better neurological outcome [101]. Also, a recent re-
view of animal and clinical studies suggests a benefit
of adjunctive corticosteroids therapy in HSE [102].
However, clear evidences are still lacking to translate
this approach into clinical practice. A clinical trial
evaluating a combination of acyclovir with glucocor-
ticoids is currently ongoing (German trial of acyclo-
vir and corticosteroids in herpes simplex virus
encephalitis; GACHE) [103].
Figure 2. Potential management of herpes simplex virus encepha-
litis. Antiviral agents that suppress the viral replication could be
combined with immunomodulatory drugs to reduce the exagger-
ated inflammatory response that develops in the CNS at later times
after infection. Biomarkers of inflammation should be identified
for timely administration of adjunctive immune-based therapy
Copyright © 2015 John Wiley & Sons, Ltd.
J. Piret and G. Boivin
Our group demonstrated that the administration
of glucocorticoids initiated on day 3 (at the onset of
symptoms) after intranasal infection of mice with
HSV-1 was associated with reduced viral replication
and cytokine levels in the CNS and an increased sur-
vival rate [58]. In contrast, glucocorticoids treatment
initiated the day of infection (day 0) prevented the
control of viral replication and was detrimental to
the host. Thus, contrary to other CNS infections
(e.g. bacterial meningitis) which require early ad-
ministration of steroids, this study demonstrated
that treatment with immunomodulatory drugs
should be delayed to improve the outcome of HSE.
In this respect, the modulation of the immune re-
sponse by TLR agonists or antagonists adminis-
tered before or after infection of mice, respectively,
could improve the outcome of HSE. For instance,
stimulation of TLR3 by pre-treatment of mice with
poly I:C before HSV-1 challenge reduced viral rep-
lication and the severity of infection [104]. In a
similar manner, the pre-treatment of mice with
TLR9 agonists [oligodeoxynucleotides (ODNs)
containing unmethylated CpG motifs] before
HSV-1 infection reduced brain viral load and in-
creased survival rate [105]. More clinically-relevant
data showed that treatment of mice with an antag-
onist of TLR9 given on day 3 post-infection in-
creased the survival rate likely by controlling the
inflammatory response that could be detrimental
to the host [105].
The added benefit of combining an antiviral
agent with an immunomodulatory drug for the
treatment of HSE has also been investigated in
mouse models. We reported that treatment of mice
with a combination of valacyclovir (a prodrug of
acyclovir) and an anti-TNF-α antibody (i.e.
etanercept) initiated on day 3 post-infection signifi-
cantly increased survival rate compared to antiviral
therapy alone [106].
Overall, these data suggest that antiviral agents
could be combined with immune-based therapy to
improve the outcome of patients suffering from HSE.
However, biomarkers of inflammation in the blood
or in the CSF [107,108] should be identified for timely
administration of immunomodulatory therapy.
MANAGEMENT OF HSE IN CHILDREN WITH
INHERITED DEFICIENCIES IN INNATE
IMMUNITY
As in the general population, antiviral therapy
should be initiated early in children with inherited
Rev. Med. Virol. 2015; 25: 300–319.
DOI: 10.1002/rmv
Innate immune response to herpes simplex virus
deficiencies of the innate immune system present-
ing suspected or proven HSE [19]. It has been re-
ported that the clinical penetrance of TLR3
pathway deficiencies is incomplete as some family
members of affected children did not develop
HSE despite HSV-1 infection [109]. The age at infec-
tion may be a key factor for the development of
HSE in genetically predisposed children probably
because of an immature immune system [7]. There-
fore, children in at risk families could be provided
with prenatal or neonatal genetic testing to allow
appropriate follow-up and clinical care until ado-
lescence or documented HSV-1 seroconversion.
Moreover, children with an inherited deficiency in
TLR3 immunity suffering from HSE should be care-
fully followed because of an increased risk of recur-
rences [77]. Such children may benefit from
antiviral prophylaxis. The use of adjunctive
immune-based therapy in such patients should re-
inforce the innate immune response rather than re-
ducing an overzealous inflammation that would
develop at later times after the infection. For in-
stance, it was suggested that children with first ep-
isode of HSE or HSE relapses associated with a
genetic defect in IFN-α production or a partial de-
fect in IFN-α response would benefit from a combi-
nation therapy of acyclovir and recombinant IFN-α
2b [110]. In this respect, a combination of acyclovir
and IFN-α administered on day 1 or 2 after infec-
tion with HSV showed a 30% increase in the sur-
vival rate of mice compared to those treated with
acyclovir alone [111].
CONCLUSIONS AND PERSPECTIVES
The innate immune system is involved in the sens-
ing of HSV and induces the production of type I
IFN as well as pro-inflammatory cytokines and
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