Review Article Evasion of Early Antiviral Responses by Herpes Simplex Viruses - Hindawi

17 Pages·2015·2.17 MB·English

Hindawi Publishing Corporation
Mediators of Inflammation
Volume 2015, Article ID 593757, 16 pages
http://dx.doi.org/10.1155/2015/593757
Review Article
Evasion of Early Antiviral Responses by Herpes Simplex Viruses
PaulaA.Suazo,1FranciscoJ.Ibañez,1AngelloR.Retamal-Díaz,1MarysolV.Paz-Fiblas,1
SusanM.Bueno,1,2AlexisM.Kalergis,1,2,3andPabloA.González1
1MillenniumInstituteonImmunologyandImmunotherapy,DepartamentodeGene´ticaMolecularyMicrobiolog´ıa,
FacultaddeCienciasBiolo´gicas,PontificiaUniversidadCato´licadeChile,8331010Santiago,Chile
2INSERMUMR1064,44093Nantes,France
3DepartamentodeInmunolog´ıaCl´ınicayReumatolog´ıa,EscueladeMedicina,FacultaddeMedicina,
PontificiaUniversidadCato´licadeChile,8331010Santiago,Chile
CorrespondenceshouldbeaddressedtoPabloA.Gonza´lez;[email protected]
Received12January2015;Accepted10March2015
AcademicEditor:MarjaOjaniemi
Copyright©2015PaulaA.Suazoetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Besidesovercomingphysicalconstraints,suchasextremetemperatures,reducedhumidity,elevatedpressure,andnaturalpredators,
human pathogens further need to overcome an arsenal of antimicrobial components evolved by the host to limit infection,
replicationandoptimally,reinfection.Herpessimplexvirus-1(HSV-1)andherpessimplexvirus-2(HSV-2)infecthumansatahigh
frequencyandpersistwithinthehostforlifebyestablishinglatencyinneurons.Togainaccesstothesecells,herpessimplexviruses
(HSVs)mustreplicateandblockimmediatehostantiviralresponseselicitedbyepithelialcellsandinnateimmunecomponentsearly
afterinfection.Duringtheseprocesses,infectedandnoninfectedneighboringcells,aswellastissue-residentandpatrollingimmune
cells,willsenseviralcomponentsandcell-associateddangersignalsandsecretesolublemediators.Whiletype-Iinterferonsaim
atlimitingvirusspread,cytokinesandchemokineswillmodulateresidentandincomingimmunecells.Inthispaper,wediscuss
recentfindingsrelativetotheearlystepstakingplaceduringHSVinfectionandreplication.Further,wediscusshowHSVsevade
detectionbyhostcellsandthemolecularmechanismsevolvedbythesevirusestocircumventearlyantiviralmechanisms,ultimately
leadingtoneuroninfectionandtheestablishmentoflatency.
1.Introduction of our ancestors, as proposed by recent phylogenetic anal-
yses [7]. Symptomatic manifestations of HSVs have been
Herpesviruses are frequently found in humans, although described as early as 400 BC and these viruses are often
theirprevalencesignificantlyvariesdependingonethnicity, considered the oldest viruses to be studied in the history
sex,andgeographicallocationofindividuals,amongothers of science [8]. While HSV-1 is estimated to infect up to
[1–5]. Currently, eight Herpesviridae family members are one-third of the world population, HSV-2 infects nearly
known to infect humans: herpes simplex viruses (HSV) -1 500 million people around the globe with more than 20
and -2 (HSV-1, HHV-1 and HSV-2, HHV-2, resp.), vari- million new cases occurring every year [4]. Importantly,
cellazostervirus(VZV,HHV-3),EpsteinBarr(EBV,HHV- HSV-1 is the foremost important cause of infectious blind-
4), cytomegalovirus (CMV, HHV-5), human herpesvirus 6 ness in developed countries and has gained importance in
(HHV-6), human herpesvirus 7 (HHV-7), and Kaposi primary genital infection, surpassing in many cases HSV-
sarcoma-associatedvirus(KSVorHHV-8).Allherpesviruses 2 [9–22]. Nevertheless, because HSV-2 recurs significantly
harbor large genomes encoding >70 genes and share the more often than HSV-1 in the genitalia, HSV-2 remains
capacitytoestablishlifelongpersistentinfectionsinthehost overall the most frequent cause of genital ulcers worldwide
([6]andNCBI). [23–26]. It is important to bear in mind that HSV-1 and
Human infection with herpes simplex viruses (HSVs) HSV-2 also produce several other pathological conditions,
traces far back, even before the intercontinental migration suchasencephalitis,conjunctivitis,zosteriformskinlesions,
2 MediatorsofInflammation
pneumonia, and systemic infections that compromise vital its receptors: nectin-1 (PVRL1; poliovirus receptor-related 1)
organs[1].Animportantconcernregardinggenitalinfection expressed on the surface of most host cells or alternatively
with HSV is its association with increased HIV infection. HVEM (Herpesvirus Entry Mediator, TNFRSF14), mainly
Indeed, genital infection with HSV has been suggested to expressedonimmunecells[54,55].Furthermore,3-O-sulfate
increaseupto3-4timesthesusceptibilityofacquiringHIV HS has also been suggested as a potential receptor for
[27–29], which has been proposed to be mediated, at least gD, although its physiological relevance requires additional
in part by soluble mediators at the infection site [30, 31]. research [56]. Binding of gD to its receptors is thought to
Furthermore,individualscoinfectedwithHSVandHIVshed induceconformationalchangesleadingtothefunctionalacti-
significantlymorethesevirusesthanindividualswithsingle vationofacomplexformedbygH/gL[57].ActivatedgH/gL
viralinfections[32–34]. complex would in turn then promote changes in gB that
Importanteffortshavebeeninvestedinthepast20years activatethefusogenicpropertiesofthisproteinandmediate
on the development of a vaccine against HSVs. However, the fusion of viral and host cell membranes [58, 59]. As an
potential vaccine formulations that have reached the clinic alternativepathway,HSVscanentercellsthroughendocytic
have proven ineffective at preventing infection or reducing vesicles[60,61].Inbothcases,fusionofmembranespromotes
virus shedding [35, 36]. Discouraging results derived from the entry of the capsid and accompanying viral proteins
the latest HSV-2 vaccine clinical trial, which used a viral (tegument)intothecytoplasm[62].Thetegumentisacom-
subunitformulation,haveledtonewdebatesinthefieldand plex mesh of >20 proteins beneath the envelope that wraps
rethinkingontheroleofneutralizingantibodiesinprotecting the viral capsid and contains molecular determinants that
againstHSV-2,aswellastheneedforcorrelatesofprotection mediate,amongothers,theinhibitionofcellulartranslation
[37–39].Indeed,somewhatunexpectedresultswereobtained andapoptosis[62,63].Oncereleasedintothecytoplasm,the
with a subunit vaccine consisting of HSV-2 glycoprotein D capsid associates with microtubules through two tegument
(gD)plusanadjuvant,whichwasfoundtobemoreefficacious proteinsVP1-2(encodedbyUL36)andUL37andthentravels
against HSV-1 than against HSV-2-induced genital disease to the outer nuclear membrane to bind to the host nuclear
[40,41].Again,thesedataareleadingtonewparadigmshifts porecomplex(NPC)toreleasetheviralDNAintothenucleus
in the field that hopefully will translate into novel vaccine [62,63].NucleoporinNup358hasbeenassociatedwiththis
approaches that could eventually reach the clinic. The lack process by docking VP1-2 onto the nuclear pore complex
ofaneffectivevaccineagainstHSVshasflourishedontothe and facilitating the release of viral DNA into the nucleus
developmentofnovelmicrobicidesagainsttheseviruses[1]. through this macromolecular complex [64]. Once released
into the nucleus, the viral DNA is transcribed by means of
HSVestablishesalifelonginfectioninthehostbyinfect-
thehostRNA-polymeraseIIactivity[65,66].However, not
ingneuronsandpersistinglatentlyinsidethesecells[42,43].
all HSV genes are expressed synchronously but instead in
Because sensorial nervous termini innervate the skin and
four consecutive rounds of transcription. First, immediate
mucosae, infections at these sites with HSVs can lead to
early genes (alpha) are transcribed, many of which encode
neuroninfectionwithasignificantlyhighfrequency[44,45].
for proteins contributing to immune evasion and work as
Indeed,HSVscanreadilygainaccesstoneuronssomewhat
factors controlling cell translation [67]. Then, follows the
earlyafterinfectingepithelialcells,becausethesecellsinteract
transcriptionofearlygenes(beta)thatarerequiredforDNA
closely.Nevertheless,torestrictvirusaccesstoneuronsand
replication [68]. Finally, early late and late genes (gamma-
othertissues,thehosthasevolvedanarsenalofantimicrobial
1 and gamma-2) are transcribed, which mainly encode for
determinants that aim at blocking infection, progression
structuralcomponentsofvirions,suchascapsid,tegument,
of infection, and microbe replication. However, as masters
and surface proteins [69, 70]. These proteins can work as
of immune evasion, HSVs encode molecular determinants
wellasimportantimmuneevasiondeterminants(seebelow).
that promote their stealth and overcome host defenses by
To generate new virions, capsid proteins migrate from the
overridingseveraloftheantiviralelementsofthehost.
cytoplasmintothenucleustoassemblewithviralDNAand
acquireatthislocationalayeroftegumentproteins.Unlike
2.HSVInfectiousCycle other viruses, HSVs do not alter nuclear pores on exit but
ratherundergoenvelopmentintheinnernuclearmembrane
Herpessimplexvirusesareenvelopedviruseswithnumerous to form an enveloped capsid [71]. The capsid then travels
proteins and glycoproteins embedded on their exterior; through the perinuclear space and immediately fuses with
whether 11 of the viral glycoproteins encoded by the viral theouternuclearmembranethankstoglycoproteinsgBand
genome are present on the virion surface remains to be gH,exposingategument-recoveredcapsidintothecytoplasm
thoroughly defined [46, 47]. Nevertheless, at least five viral [72].Onceinthecytoplasm,thecapsidisfurthercoatedwith
glycoproteinshavebeenimplicatedinviralentry:glycopro- additionaltegumentproteinsandisonceagainenvelopedin
teinB(gB),gC,gD,gH,andgL[48,49].gBactsbothasaviral thetrans-Golginetwork[73].Fromhere,virionsareexported
attachmentproteinandfusionproteinbybindingtoheparan in vesicles to the cell surface and secreted. Although host
sulfates(HS)onthesurfaceofsusceptiblehostcells[50]and tetherin(Bst-2orCD317)hasbeenshowntoblocktherelease
alsoisknowntobindtopairedimmunoglobulin-liketype2 of certain enveloped viruses from the cell surface, the HSV
receptor (PILR) alpha [51, 52]. A similar function has been proteinvhs(virionhostshutoffprotein,UL41)cancounteract
describedforgCinvirusattachment,althoughonlyforHSV- the antiviral function of this protein by depleting it [74].
1 [53]. After gB-mediated attachment,gD bindsto eitherof Noteworthy,HSVscanalsopropagatedirectlyontoadjacent
MediatorsofInflammation 3
gB
gH
A ? Unknown gH/gL gH/gL B
gL
TLR2+ 𝛼(cid:4)𝛽3 𝛼(cid:4)𝛽3
gD
Nectin-1 C MYD88
TLR3
DAI
polyI:C
cGAS NH2
N N CpG Mediators
F IFI16 N CH3 E ICP0
CH3
vhs G 2AIM 2AIM asome TLR7IM TLR9 pN50F𝜅pB65 IRF3 IRF7
m
D
MDA5 PYDPYD PYDPYDflam CIFyNtoskines
RIG-1 CARDCARD CARDCARDIn Mediators p50 p65
H Caspase-1 ICP0 IRF3IRF7 ICFyNtoskines
TNF-𝛼 IL-6 IL-10
Figure1:HSVsinterferewithhostdetectionofviraldeterminants.Immuneandnonimmunecellsexpressanarrayofpathogenrecognition
receptorsintendedtodetectmicrobes,whichultimatelyleadtoNF-𝜅BandIRFtranslocationintothenucleusandsecretionofantiviral
molecules,suchasinterferonsandcytokines.A:HostcellscansenseHSVdeterminantsthroughTLR2,althoughthespecificviralelements
detectedbythisreceptorarecurrentlyunknown.IntracellularsignalingthroughTLR2canoccurwiththehelpofintegrin𝛼]𝛽3-bindingafter
thisreceptorbindswiththeHSVcomplexgH/gL.B:Alternatively,integrin𝛼]𝛽3cansignalintracellularlyonitsownaftergH/gLbinding.
ThisprocesscanbeinterferedbyICP0C:TLR3,D:TLR7,andE:TLR9engagementbyactivatingligands,suchaspolyI:C,imiquimod(IM),
andCpG-ODN,respectively,havebeenshowntoplayfavorablerolesagainstHSVinfectionbyinducingactivatingpathwayswithincellsthat
leadtothesecretionofantiviralmolecules.F:NucleicacidsgeneratedduringHSVinfectioncanalsobedetectedbyhostintracellularsensors,
suchasDAI,cGAS,andIFI16.G:TheRIG-1/MDA5complexcanalsodetectvirus-derivednucleicacids;howeveritsfunctionisblockedby
viralvhs.H:Finally,theinflammasomeisactivatedbyHSVdeterminants,althoughHSVICP0cancounteractitsactivityandnegatively
modulateitsfunction.
cells through cell-cell interactions. In these circumstances, [79]. An important family of PRRs is Toll-like receptors
virus components are directed to the interface of cell-cell (TLRs),whichuponbindingwithmicrobeelementsleadto
regions. This type of infection is used by HSVs to infect intracellular signaling cascades that promote early antiviral
T cells, which has been shown to occur through infected cellularresponsesandthesecretionofsolublemediatorsthat
fibroblastsinvitro[75,76].Thistypeofinfectionismediated activateinfectedandnoninfectedneighboringcells,aswellas
through a process called virological synapse and provides theimmunesystem[80–84].
the virus a safe haven from neutralization by antibodies or It has been shown that HSVs induce the activation of
complement(seebelow)[77,78]. TLR2 in primary vaginal epithelial cells and also immune
cells,suchasdendriticcells(DCs).Interestingly,ithasbeen
3.EvasionofHSVSensingbyHostReceptors suggested that in keratinocytes, neural cells, and epithelial
cellsTLR2-mediatedeffectsaftervirusinfectionrequirethe
Immune and nonimmune host cells express an array of cooperationof𝛼]𝛽3-integrin,likelyduetothebindingofthe
surfaceandintracellularreceptorsintendedtosensemicro- HSVgH/gLcomplextothisintegrin,leadingtoNF-𝜅Bacti-
bial elements and initiating local and systemic antimicro- vation,interferonproduction,andIL-10secretion(Figure1)
bialresponses.Suchreceptors,termedpathogenrecognition [85, 86]. In DCs, the activation of TLR2 induces a cell
receptors(PRRs),recognizePathogenAssociatedMolecular response that leads to the downstream activation of NF-
Patterns(PAMPs),whichconsistamongothersofmicrobe- 𝜅B and the transcription of immunomodulatory cytokines,
derivedmolecules,suchaslipids,proteinsandnucleicacids such as IL-6, IL-8, IL-10, IL-12, and TNF-𝛼 [87]. Another
4 MediatorsofInflammation
study with DCs also showed that HSV recognition by involved in the favorable results observed against HSV in
TLR2promotedIL-6andIL-12secretionandproposedthat otherstudies[101].
this cytokine outcome was mediated, at least in part, by TLR9hasalsobeenshowntoplayrolesinHSVinfection,
TLR9 modulation, suggesting a previously uncharacterized althoughsimilartoTLR3andTLR7,becauseTLR9agonists
mechanism for sequential recognition of viruses via TLR2 can positively influence the antiviral response against this
−/−
through TLR9 [88]. Consistent with this notion, TLR2 pathogen. Indeed, mice pretreated intranasally with TLR9
knockout mice secrete low levels of MCP-1, a chemokine agonists,suchasCpG-oligodeoxynucleotides(CpG-ODNs),
generallyinducedafterTLR9engagement[89].Importantly, show reduced secretion of inflammatory cytokines, such as
TLR2−/−knockoutmicedisplayprolongedsurvivalafterHSV CCL2,IL-6,andCCL5,andreducedviralloadsinthebrain,
infection,ascomparedtowild-typeandTLR4−/− knockout resultinginmildencephalitisandincreasedsurvivalrates,as
mice.Despitereducedmortality,viralloadsremainedsimilar compared to nontreated mice (Figure1) [103]. Additionally,
inTLR2-knockoutandwild-typeanimals[90].Ontheother treatment with CpG-ODN containing unmethylated CpG
−/− provides protection against lethal vaginal challenge with
hand, microglia from TLR2 mice display delayed and
HSV that was probably mediated by an intricate crosstalk
attenuated production of reactive oxygen species (ROS)
betweenplasmacytoidDCs(pDCs)andvaginalstromalcells,
followingviralinfectionandsufferlesserneuronaloxidative
as well as type-I IFNs [104–106]. Similar to the findings
damageinmixedneuralcellcultures,ascomparedtoHSV-
described with TLR3 and TLR7, these results suggest that
infectedcellsfromwild-typeanimals[91].
modulating TLR9 signaling could be a promising strategy
TLR3 has also been described to play a role in HSV
forlimitingHSVinfectioninthehost,althoughresultsfrom
infection,especiallyforneuronsandduringviralbraininfec-
another group suggest that the antiviral effects mediated
tion.Forinstance,ithasbeenshownthatTLR3deficiencies
−/− by TLR9 antagonists might not necessarily be mediated
(TLR3 ) render astrocytes permissive to HSV infection,
uniquely by intracellular events linked to TLR9 signaling
facilitating the establishment of CNS infection in animals.
[107].Nevertheless,theresultsobtainedwithTLR9agonists
Consistently,itwasshownthatTLR3expressedinastrocytes
suggestthatactivatingthisTLRmightbeausefulstrategyfor
provided early control of HSV infection after viral entry
controlling pathological responses induced by HSVs [108].
into the central nervous system and induced type-I IFN
When combined with antivirals, such as acyclovir or anti-
responses in these cells. Remarkably, this TLR3 deficiency
inflammatorymolecules,thisstrategycouldimprovecurrent
didnotseemtoaffectinnateimmuneresponses[92].Other
therapiesagainsttheseviruses[103,109].
studieshaveshownthatastrocyteinfectionwithHSVleads
to TLR3 engagement and NF-𝜅B activation, upregulating Importantly,HSVsalsoinducetheactivationofnon-TLR
the expression of TNF-𝛼 and IL-6 with antiviral functions sensors in target cells. Namely, primary vaginal epithelial
attributedtothesetwomolecules(Figure1)[93].Ontheother cells display increased activation of DNA sensors, such as
hand,studiesperformedinhumanscarryingmutationsthat DAI (DNA-dependent activator of interferon) and IFI16
negatively modulate TLR3-mediated immunity have shown (interferon-inducible 16), which trigger the secretion of IL-
that these individuals are more prone to HSV encephalitis 6 (Figure1) [110]. Another non-TLR host sensor includes
[94–96]. Consistent with these findings, a study with ex 𝛼V𝛽3-integrin,mentionedabovewithTLR2,whichwasalso
vivodifferentiatedneurons,astrocytesandoligodendrocytes recently described to function as a major sensor of HSVs
derived from pluripotent stem cells from individuals with per se and activator of innate immunity by relocating the
TLR3 deficiencies were shown to be more susceptible to viruses’nectin-1receptortocholesterol-richmicrodomains,
HSV infection in vitro than control cells and displayed thus,enablingvirusuptakeintodynamin2-dependentacidic
compromisedinterferonsecretion.Interestingly,theseeffects endosomes [111]. 𝛼V𝛽3-integrin interacts with HSVs gH/gL
depended significantly on the cell types analyzed [97]. On complexes and is thought to signal at least through two
the other hand, mice pretreated either intravaginally or pathways,onemediatedbyTLR2withtheactivationofNF-
intraperitoneally with agonists for TLR3, such as polyI:C, 𝜅B and consequently induction of type-I interferons and
suffersignificantlylessvirusburdenuponintravaginalviral another involving sarcoma- (SRC-) spleen tyrosine kinase-
challengethannontreatedanimals,suggestingthatactivating (SYK-) caspase recruitment domain-containing protein 9-
thispathwaywouldplayfavorablerolesagainstHSVinfection (CARD9-)TRIF(TIR-domain-containingadapter-inducing
(Figure1)[98]. interferon-𝛽), which affects interferon regulatory factor 3
As with TLR3, pretreating animals with TLR7 agonists, (IRF3) and IRF7 (Figure1) [85, 86]. Importantly, the HSV
such as imiquimod, has also been shown to significantly viral protein ICP0 can counteract these 𝛼V𝛽3-integrin sig-
reduce HSV burden in the genital tract after viral infection naling pathways to impair sensing of HSVs by infected
(Figure1)[99].Becauseoftheseresults,imiquimodhasbeen cells [86]. A recent study suggests that TLR signaling via
tested in humans, particularly against HSV strains that are MyD88andTRIFisexpendableforcontrollingHSVinfection
−/− −/− −/−
resistanttoacyclovirinimmunocompromisedpatients,with and spread. Indeed, MyD88 , TRIF , and MyD88 -
−/−
favorableresults[100–102].However,itisimportanttonote TRIF double knockout mice displayed similar levels of
that another study found that imiquimod produced IFN- HSVreplication,whencomparedtowild-typemice,although
independent anti-HSV effects in nonimmune cells, which thisparticularstudywasfocusedonHSVcornealinfection.
was independent of TLR signaling and IFN production, Importantly,theDNAsensorIFI-16/p204wasidentifiedhere
suggestingthatTLR7islikelynottheonlyactivationpathway to be key for the activation of IRF3 and IFN-𝛼 production
MediatorsofInflammation 5
forviralcontainment[112].Consistently,silencingthegenes neuronsandepithelialcellsafterviralinfection(Figure2(a))
that encode for IFI16/p204 inhibits the activation of IRF3 [119–121]. Finally, US3 an HSV protein kinase conserved
and NF-𝜅B in response to HSV DNA [113]. Furthermore, a throughoutalphaherpesviruseshasalsobeenshowntoplaya
recentstudyshowedthatIFI16depletionwasassociatedwith keyroleinblockingapoptosisinducedbyviralgeneproducts
increased HSV yield, while its overexpression reduced the and exogenous agents in epithelial cells. The antiapoptotic
amountofvirusobtainedincellcultures.ChIPassaysfound effects of US3 would be mediated through its interaction
that IFI16 binds to HSV promoters and that cells devoid of with programmed cell death protein 4 (PDCD4), which is
thisproteindisplayincreasedamountsofhostproteinsthat retainedinthenucleusofinfectedcells(Figure2(a))[122].
promote viral gene transcription at these locations. These Nevertheless, other HSV proteins have been proposed
findingssuggestthatIFI16possessesantiviralfunctionsand toinduceapoptosisandnecrosisinhostcells.Forinstance,
negativelymodulatesHSVtranscriptionafterbindingtoviral HSVhasbeenshowntoinducenecrosisinmousefibroblast
DNA[114].Anotherintracellular,non-TLRreceptorinvolved cells (L929 cells) mediated by the interaction between the
in the detection of HSV determinants is cyclic guanosine viral ribonucleotide reductase large subunit ICP6 and RIP3
monophosphate-adenosine monophosphate (cGAMP) syn- (receptor-interacting kinase 3) through RHIM domains,
thase(cGAS),anovelcytosolicDNAsensor(Figure1).This which activate MLKL (mixed lineage kinase domain-like
proteinhasbeenshowntodetectHSVDNAleadingtotype- protein).Consistently,anHSVICP6deletionmutantfailedto
I IFN (IFN-I) production in fibroblasts, macrophages, and causeeffectivenecrosisofHSV-infectedcellsandmicelack-
dendriticcellsandmicedeficientforcGassuccumbtodeath ing RIP3 exhibited severely impaired control of HSV repli-
afterinfectionwiththisvirus[115].Intracellularnucleicacid cationandpathogenesis,highlightingtheimportanceofthe
sensors RIG-I and MDA5 (retinoic acid-inducible gene 1 latterinlimitingviruspathology[123].Noteworthily,another
andmelanomadifferentiation-associatedprotein5)alsoplay study showed that early after HSV infection, natural killer
antiviralrolesininfectedcells,yetvhscanselectivelyinhibit cells(NKcells)sufferapoptosisthroughFas/FasLwhenthese
the expression of these molecules and prevent downstream cells interact with HSV-infected macrophages (Figure2(b))
IRF3dimerization,aswellasthetranslocationofthiscomplex [124].
into the nucleus (Figure1). By doing so, vhs can block Similarly,HSVinfectionofdendriticcellsinducesapop-
signalingmediatedthroughnon-TLRpathways[116]. tosis early after virus entry, particularly after the release of
Another mechanism by which host cells can sense and immunomodulatorycytokines[125,126],andtheviralpro-
initiate antiviral responses is through the activation of the tein𝛾34.5caninterferewithDCautophagosomematuration,
inflammasome.Theinflammasomeisamultiproteincomplex which is thought to play antiviral functions in these cells
involvedintranslatingpathogenrecognitioneventsintothe by degrading virus determinants (Figure2(b)) [127, 128].
secretionofinflammatorymolecules,suchasIL-1𝛽.Relevant A similar role for autophagy has been proposed in the
inflammasome sensors include NLRP3 and AIM2 in the contextofHSVinfectioninneuronsasanalternativetoIFN
cytoplasm of cells and the nuclear sensor IFI16, discussed responses, which would likely result in the death of these
above.RecentstudieshaveshownthatHSVcaninduceearly cellsordetrimentaloutcomesforthehost.Indeed,neurons
activation of the inflammasome and then, later on, inhibit from dorsal root ganglia require autophagy to limit HSV
itsfunctionduringactiveinfection[117].Indeed,fibroblasts replicationinvivoandinvitro[128].
infected with HSV display activated IFI16 and NLRP3 and Antiviral functions in host cells are also mediated by
secrete IL-1𝛽 early after infection, although later on IFI16 Protein Kinase R (PKR), which phosphorylates the trans-
is targeted to the proteasome by ICP0, likely releasing the lation initiation factor EIF2A as a mechanism to inhibit
breakthatIFI16imposesonthetranscriptionofHSVgenes the translation of RNA messengers upon viral infections.
[114,117].Subsequently,NLRP3andAIM2remainunaltered Importantly,thishostproteinhasbeenshowntoplayakey
incellswithaninhibitedinflammasomeandlittlesecretion roleincontrollingHSVreplicationinvitroandinvivo[129,
ofmatureIL-1𝛽[117]. 130]. However, HSVs have evolved molecular determinants
that negatively modulate PKR function. For instance, viral
𝛾34.5andUS11havebeenproposedtoinhibittheactivityof
4.ModulationofCellViabilityandEarly PKR to promote the translation of viral proteins (Figure3)
AntiviralResponse [131,132].Furthermore,HSVshaveevolveddeterminantsthat
preferentially block the translation of host molecules over
Sensing of microbial components by immune and nonim- viral genes, in such a way to impair their antiviral activity.
mune cells can lead to cell apoptosis, as a host strategy to Indeed, HSVs vhs protein can mediate the degradation of
blockvirusreplicationandspreadwithincells.Importantly, host messenger RNA through their ribonuclease activity
HSVsencodeviraldeterminantsthatblockordelaytheonset (Figure3) [133]. The spatial-temporal delivery of vhs has
ofapoptosisininfectedcells,likelyasamechanismtoextend evolvedinsuchawaytodisplay optimalactivityearlyafter
theviabilityofitssubstrateforreplication.Thisprocesshas infectionforhamperinghostmRNAtranscriptionandnotto
beenproposedtobemediatedbyviralglycoproteinssuchas alterviralmRNAstranscribedlateron[134].
gJandgD,asvirusmutantslackingeachoneoftheseproteins EarlysensingofviraldeterminantsbyhostPRRswillgen-
initiated apoptotic cascades in epithelial cells (Figure2(a)) erallyleadtotheactivationofinterferonpathwaysthataimat
[118].Furthermore,theviralproteinsICP10PKandUL14have impairingvirusreplicationanditssheddingwithinthehost
alsobeenshowntopreventapoptoticprocessestriggeredin [135].AlthoughcellsinthegenitaltractinfectedwithHSV-2
6 MediatorsofInflammation
EPITHELIAL CELL
Nectin-1 Apoptosis
US3
UL14
gD
gJ ICP0 PDCD4
UL14
ICP0
vhs ICP6
ICP6
Necrosis
Viral DNA
RIP3
Tetherin
FIBROBLAST
(a)
DENDRITIC CELL 1
n-
Necti
𝛾34.5
Autophagosome
HSV genes
NK CELL
Fas
FasL
MACROPHAGE
(b)
Figure2:HSVsinterferewithcellviability.HSVsencodedeterminantsthatmodulatecellviability.(a)Withinepithelialcells,HSVcanextend
thesurvivalofcellsbyblockingapoptosisthankstoviralproteins,suchasgD,gJ,UL14,ICP0,andUS3.Tetherin,ahostantiviralfactorinvolved
inblockingvirusreleasefromthesurfaceofinfectedcells,isblockedbyHSVvhs.Contrarily,fibroblastsdisplaynecrosisuponinfectionwith
HSV,whichwouldbemediatedbyICP6.(b)DendriticcellsdisplayapoptosisearlyafterinfectionwithHSVsbyunknownviraldeterminants.
Theautophagosome,whichmediatesviruscontrolintheseandothercells,suchasneurons,isinhibitedbytheviralprotein𝛾34.5.HSValso
inducesapoptosisofNKcells,albeitthroughFas/FasLinteractionsbetweenthesecellsandHSV-infectedmacrophages.
MediatorsofInflammation 7
IFN
Nectin-1
IFNR
A
Host
Host mRNAs
sensors
vhs
EIF2A TRAF3 STAT-1
P UL36 P D
Ub Ub P
PKR C STAT-2 ICP27
US3
US11
𝛾34.5
B
IRF9
IRF3
ICP0
STAT-1
P
P
STAT-2
IFNs IFN-effectors
IRF3 IRF9
Host DNA
ICP27, US11
US3,𝛾34.5, ICP0
Viral DNA
Figure3:HSVsinterferewiththeinductionoftype-Iinterferonsandinterferonsignaling.A:HSVvhsproteinsinterferewithcellprotein
translationbyspecificallydegradinghostmRNAs.B:ViralUS11and𝛾34.5interferewithhostPKRfunction,byimpairingitscapacityto
phosphorylateEIF2A,whichblockstranslationwithininfectedcells.C:HostsensorsactivateTRAF3afterdetectingHSVdeterminants,
whichnormallyleadstoIRF3activation.However,UL36interfereswithTRAF3ubiquitinationblockingitsIRF3-activatingcapacity.ICP0
andUS3alsointerferewithIRF3activation.ImpairedIRF3functionwillresultinpoorsecretionofinterferonsbyinfectedcells.D:Viral
ICP27interfereswithSTAT-1signalingmediatedbyIFNR,whichwouldotherwiseleadtothesecretionofantiviraleffectors.
produceinterferonsinresponsetothisvirus,themagnitude [138]. Interference with host interferon pathways would be
ofthisresponseisgenerallyhamperedintheinfectedtissue, mediated, at least in part by the early viral protein ICP0,
suggestingthatthesemoleculeslikelyplayfavorableantiviral whichcanimpairIRF3functionandblockthetranscription
roles [136]. Indeed, biopsies obtained from individuals of genes regulated by this transcription factor [137]. Addi-
infectedwithHSVshowextremelylowlevelsoftype-IIFNs tionally, HSV ICP27 also inhibits type-I IFN signaling and
(IFN-𝛼andIFN-𝛽),despitethepresenceofalargenumber interferes with nuclear accumulation of STAT-1 (Figure3)
of cells capable of synthesizing these mediators, which [139].Furthermore,theHSVSer/ThrkinaseUS3canhamper
suggests alterations in the host interferon response during IFN-𝛽 production by hyperphosphorylating IRF3 and by
HSVinfection[137].Consistentwiththisnotion,type-IIFN blocking the dimerization and nuclear translocation of this
receptor(IFNAR)knockoutmiceinoculatedinthefootpads factor(Figure3)[140].Similarly,thetegumentproteinVP16
with HSV manifest systemic viral infections that affect can also abrogate IFN-𝛽 expression by inhibiting NF-𝜅B
the lungs, liver, and spleens, although disease is nonlethal and IRF3 activation by impairing the recruitment of the
8 MediatorsofInflammation
coactivatorCBP,withoutinterferingwithIRF3dimerization, Taken together,HSVs haveevolvedstrategiesto bothblock
nucleartranslocation,oritsDNAbindingactivity(Figure3) and promote the activation of NF-𝜅B within infected cells.
[141].Yet,anothermechanismbywhichHSVinhibitsIFN-𝛽 Whether these opposing effects depend on the cell types
expression is through the deubiquitination of TRAF3 by targetedbythesevirusesordifferentstagesoftheinfectious
the viral ubiquitin-specific protease UL36, which inhibits cycle requires further study. Nevertheless, these findings
stimuli-inducedIRF3dimerization,promoteractivation,and highlighttheimportanceofNF-𝜅BmodulationbyHSVsafter
thetranscriptionofIFN-𝛽(Figure3)[142].Asnoted,HSVs infection.
have evolved redundant and nonredundant mechanisms to Despite interference with NF-𝜅B activity, cells infected
specificallyimpairthefunctionofhostmoleculesthatarekey with HSV nonetheless secrete numerous modulatory
fortheexpressionofantiviralmolecules,namely,interferons. cytokines and chemokines after infection or at the site
TheimportanceofIFNsincontrollinginfectionbyHSVs of inflammation. For instance, HSV has been shown to
ishighlightedbythefactthatthefrequencyofgenitalherpetic induce the secretion of CCL2, IL-8, IL-6, and TNF-𝛼 in
recurrences can be reduced in patients by applying topical primary endometrial genital epithelial cells [155]. In vivo,
IFN-𝛼, which also reduces viral dissemination [143]. More- HSV promotes CXCL9 expression in the cervical mucus of
over,therecentlydescribedinterferonIFN-𝜀,characterizedas HSV-positive women [156]. Importantly, this chemokine
atype-IIFNconstitutivelyexpressedbyepithelialcellsinthe and CXCL10 have been shown to play important roles
femaleandmalereproductivetract,isproposedtobeapotent against HSV in CNS infection in the mouse model, likely
antiviral host mediator that likely contributes to control of byrecruitingNKandcytotoxicTcellstotheinfectedtissue
HSV infection [144, 145]. However, the exact mechanism [157]. Similarly, a recent study proposed that CXCL10 is
by which IFN-𝜀 exerts its anti-HSV effects remains to be needed for establishing protective immunity against HSV-2
determined. Importantly, expression of IFN-𝜀 varies with genital infection after vaccination with an attenuated HSV
the female hormonal cycle and seems to be limited to cells strain [158]. CCL2 induced upon HSV infection has been
belongingtoreproductiveorgans[145,146]. attributedafavorableroleincornealinfectioninthemouse
−/−
model. Indeed, CCL2 mice were unable to contain the
virus and failed to recruit inflammatory monocytes to
5.SecretionofImmunomodulatoryMediators the infection site [159]. Furthermore, CCL2 expression
EarlyafterHSVInfection driven by IFI16 recognition of HSV has been described to
facilitatetherecruitmentofinflammatorymonocytestothe
After HSV has blocked immediate host antiviral responses, infectionsite,assilencingofp204/IFI-16resultedintheloss
whichrelyonthesensingofmicrobeelementsandearlyinter- of CCL2 production and significantly more HSV shedding
feronresponses,celldamageresultingfromvirusreplication [159]. As indicated above, another cytokine induced after
likely spreads virus-elicited danger signals and damage- HSV infection is IL-6. Noteworthily, a protective role
associated molecular patterns (DAMPs) onto other nonin- has been attributed to this cytokine in microglia, likely
fectedcells[117].Theseneighboringcells,aswellaspatrolling through downstream signaling of Signal Transducer and
immune cells, may sense these danger elements and initi- Activator of Transcription 3 (STAT3), although the precise
ate cytokine and chemokine responses that will modulate mechanismleadingtoitsprotectiveroleisunclear[160,161].
the milieu and other immune components [126, 147, 148]. Mast cells have also been shown to secrete IL-6 early after
Whetherthesolublemediatorsproducedinresponsetothese HSV infection, as well as TNF-𝛼, yet these cytokines were
danger signals or HSV itself promote the clearance of the not induced directly by HSV in this study but depended
virusorfavoritspersistenceandspreadinthehostislargely on supernatants from HSV-infected keratinocytes and
unclear. the IL-33 receptor on the former cells. Importantly, mice
Because cytokine secretion is generally dependent on lackingTNF-𝛼orIL-6succumbedtodeath,consistentwith
the canonical activation of NF-𝜅B, HSVs have evolved a protective role for these cytokines [162]. Contrarily, a
several molecular mechanisms to modulate the activity of recent study suggested that treating mice with anti-TNF-
this transcription factor. A recent report showed that the 𝛼 in combination with the antiviral valacyclovir could
viral DNA polymerase processivity factor UL42 interacts significantlyimprovetheprognosisofencephalitiscausedby
with p65/RelA and p50/NF-𝜅B1 to block the translocation HSV[109].
of NF-𝜅B to the nucleus in response to stimuli, such as One aspect that has brought important attention onto
TNF-𝛼 [149]. Consistently, another study found that HSV cytokines and chemokines produced after HSV infection is
ICP0inhibitsTNF-𝛼-inducedNF-𝜅Bactivation,interacting that some of the molecules secreted in the genital tract can
similarlywithp65/RelAandp50/NF-𝜅B1[150].US3hasalso favorhostinfectionbyothersexuallytransmittedpathogens,
been shown to significantly inhibit NF-𝜅B activation and such as the human immunodeficiency virus (HIV) [30].
decrease the expression of inflammatory chemokines, such Indeed, infection with HSV-2 increases 3-4 times host sus-
as IL-8 [151]. Furthermore, HSV VP16 also inhibits NF-𝜅B ceptibility of acquiring HIV and, furthermore, coinfection
activationandblocksIFN-𝛽production[141].However,other increases the shedding of both viruses [27–29, 163]. These
HSV proteins, such as tegument protein UL37, have been findingshavebeencorroboratedinamurineinfectionmodel
shown to promote NF-𝜅B activation and IL-8 secretion in [31].TheincreasedsusceptibilitytoacquireHIVafterHSV-
keratinocytes [152]. Activation of NF-𝜅B after cell infection 2infectionhasbeensuggestedtoresult,withinothers,byan
hasalsobeenreportedtofacilitateviralreplication[153,154]. increasedrecruitmentoftargetcellsforHIV,suchasdendritic
MediatorsofInflammation 9
cellsandTcellstothesiteofinfection[164,165],increased NK cells play important roles against several viral
expression of HIV-receptor molecules at the surface or pathogens;howevertheirroleinHSVinfectionisfrequently
specific cell populations [166, 167], and reduced expression debated.Althoughsomestudiesproposekeyrolesforthese
of cell surface molecules that actually promote the capture cells, others have underestimated their importance at con-
and degradation of HIV [168]. Furthermore, immune cells trolling HSV infection [172, 173]. HSV can directly activate
such as dendritic cells infected with HSV have been shown NK cells through TLR2; whether this interaction promotes
to produce soluble mediators that promote the reactivation viral clearance or not in vivo is still unclear [174]. HSV can
of HIV from cells latently infected with the latter virus also decrease the expression of NK-activating ligands such
[126].Regretfully,theidentitiesofthesolublemoleculesthat asMICA(MHCclassIpolypeptide-relatedsequenceA)on
accountfortheobservedeffecthavenotbeenidentifiedsofar. thesurfaceofinfectedcells,thusinterferingwiththeeffector
Besidesupregulatingtheexpressionofcertaincytokines activityofthesecells.Thisprocesswouldbemediatedbyalate
and chemokines, HSVs can also reduce the expression of HSVgeneproduct,whichwouldmask,internalize,orretain
certain antiviral molecules, such as the secreted leucocyte MICAintracellularly[175,176].
proteaseinhibitor(SLPI).Indeed,HSV-infectedcellssecrete NaturalkillerT(iNKT)cellsareCD1d-restrictedTcells
lessSLPI,whichreducestheinfectivityofHSVinvitro[169]. that express invariant TCR chains, as well as NK surface
Furthermore, a decrease in the expression of SLPI would markers, and are specialized in recognizing polar lipids
likelypromoteanincreaseinthesecretionofproinflamma- presentedonthesurfaceofCD1dmolecules[177].Although
torycytokines,whichareassociatedwithexacerbateddamage variations can be observed in the amount of iNKT cells
to the infected tissues [169]. Nevertheless, virus-mediated presentafterHSVinfection,changesinthenumberofcells
inhibitionofotherchemokinescouldfavorthehost,suchas and expression of markers on their surface are somewhat
CXCL2whichissecretedbymonocytesinresponsetoHSV discrete when compared to patients in the steady state,
which is known to recruit neutrophils that elicit damaging suggestingpotentialmodulationofthesecellsbyHSVs[178].
inflammatory immune responses to host cells and tissues, Furthermore, infection with HSV has been described to
namely,neurons[170]. negatively modulate the activity of NKT cells by simply
Despite the fact that HSVs have been extensively stud- directing CD1d molecules from the cell surface of infected
ied, it is surprising to note how little we know about the cellsintointracellularcompartments,thusblockingantigen
contribution of cytokines and chemokines induced upon presentation[179,180].
infectionbythisvirustoinfectionandpathology.Cytokines
and chemokines induced by HSV infection will likely play
7.ConcludingRemarks
different roles for the host, either favorable or antagoniz-
ing, depending on the tissue infected, whether it is skin,
World prevalence for HSVs is a truthful testimony of the
genitalia,eyes, or thecentralnervoussystem. Furthermore,
success of these viruses in establishing latent infection in
differences in the nature and amounts of the cytokines and
the host. Successful infection with HSVs is likely the result
chemokinessecreteduponviralinfection,aswellastheroles
of a wide array of viral determinants encoded by these
ofthesemoleculesonvirusclearanceanddisease,willlikely
viruses with the capacity to interfere with multiple host
dependonwhetherinfectionismediatedbyHSV-1orHSV-
factors intended to control early infection by pathogenic
2. High throughput techniques such as multiplex cytokine
microbes.Indeed,HSVseffectivelyblockearlycellularantivi-
arrays and the availability of numerous knockout mice for
ralmechanismsbyextendingthesurvivalofcellsthatserve
these molecules should provide new insights and valuable
as substrates, hence favoring virus production and killing
information on the role of these soluble mediators in HSV
cells that initiate and modulate effective antiviral immune
infectioninthenearfuture.
responses,suchasDCs.Additionally,thesevirusespromote
their stealth by interfering with their sensing by infected
6.HSVInterfereswithInnate cells and by mounting somewhat modest interferon and
cytokineresponsesthatfavortheirreplicationandshedding.
ImmuneFunctions
Thesephenomenawillultimatelyallowthesevirusestoreach
cellsneededforestablishinglatency:neurons.Noteworthily,
Innate immunity has evolved soluble components and spe-
important progress has been made in the last years in
cialized cells to block microbe infection, replication, and
identifyingearlyantiviralcomponentselicitedandblockedby
shedding. One such element is the complement. The com-
HSVs.Thesestudieswillhopefullyleadtotheidentification
plementiscomposedofserumproteinsthat,oncetriggered
by microbial determinants or antibody bound to ligands, anddevelopmentofdrugsthatspecificallyinterferewithviral
interact with each other in a cascade of events that lead to processes.Noteworthily,findings,suchasthoserelatedtothe
thedamagingofthesurfacesofthepathogenorcellsinfected activationofparticularTLRsthatfavorhostresponsesagainst
with the microbe. However, HSVs have evolved molecular these viruses, will undoubtedly contribute to the develop-
determinants to interfere with the function of complement mentofnovelantiviraltherapies.Indeed,potentiatingearly
protein C5 and block its downstream activating properties; antiviral functions in the host before exposure could be as
thisprocessismediatedbyglycoproteinC[78,171].Bydoing effective as novel anti-HSV microbicides currently under
so,theviruslikelyextendsitslifespanintheserumandthat development,whileaneffectivevaccineagainsttheseviruses
ofthecellsitinfects. reachestheclinic.
10 MediatorsofInflammation
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