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Review Article Evasion of Early Antiviral Responses by Herpes Simplex Viruses - Semantic Scholar PDF

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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 ConflictofInterests virus type 1 is the main cause of genital herpes in women of Natal, Brazil,” European Journal of Obstetrics Gynecology and The authors declare that there is no conflict of interests ReproductiveBiology,vol.161,no.2,pp.190–193,2012. regardingthepublicationofthispaper. [13] F. Xu, M. R. Sternberg, B. J. 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