Within
host
RNA
virus
persistence:
mechanisms
and
consequences
$Richard
E
Randall
1and
Diane
E
Griffin
2Inaprototypicalresponsetoanacuteviralinfectionitwouldbe
expectedthattheadaptiveimmuneresponsewouldeliminate
allvirallyinfectedcellswithinafewweeksofinfection.However
many(non-retrovirus)RNAvirusescanestablish‘withinhost’
persistentinfectionsthatoccasionallyleadtochronicor
reactivateddisease.Despitetheimportanceof‘withinhost’
persistentRNAvirusinfections,muchhasstilltobelearntabout
themolecularmechanismsbywhichRNAvirusesestablish
persistentinfections,whyinnateandadaptiveimmune
responsesfailtorapidlycleartheseinfections,andthe
epidemiologicalandpotentialdiseaseconsequencesofsuch
infections.
Addresses
1SchoolofBiology,UniversityofSt.Andrews,Scotland,UK 2
W.HarryFeinstoneDepartmentofMolecularMicrobiologyand Immunology,JohnsHopkinsBloombergSchoolofPublicHealth, Baltimore,Maryland,USA
Correspondingauthor:Randall,RichardE([email protected])
CurrentOpinioninVirology2017,23:35–42
ThisreviewcomesfromathemedissueonViralpathogenesis
EditedbyMichaelDiamond
http://dx.doi.org/10.1016/j.coviro.2017.03.001
1879-6257/ã2017TheAuthors.PublishedbyElsevierB.V.Thisisan openaccessarticleundertheCCBY-NC-NDlicense( http://creative-commons.org/licenses/by-nc-nd/4.0/).
Introduction
Infections with most non-retroviral RNA viruses cause characteristic signs and symptoms of an acute disease. Duringtheacutephase ofinfection,thevirusreplicates rapidlyand isshedintotheenvironmentwithspreadto newsusceptibleindividuals.Recoveryistypically associ-ated with virusclearance and establishment of varying lengthsofimmunitytore-infection.Forsuchvirusestobe maintained within a population there needs to be a continuous supply of susceptible individuals to sustain the transmission cycle. For viruses, other than endoge-nousretrovirusesandvirusestransmittedvertically,ifthe hostpopulationsizeand/ordensityissmall,aswaslikely thecaseduringmostofhumanevolutionandiscurrently
thesituationformanyanimalpopulations,thenumberof susceptible individualsmaynotremainhighenoughfor the virus to maintain itself within a host population. Conversely, if the population density is very high, for examplein batcolonies,virusspreadmaybeextremely rapidtherebyalsoleadingtoadecreaseinthenumbersof susceptibles (through theinduction oflong-lasting pro-tectiveimmunity[1]and/orthroughhighmortalityrates) to levelsbelow that requiredfor continuedvirus trans-mission[2]
Because viruses are obligate intracellular parasites that must bemaintainedin apopulation, RNAviruses have evolvedanumberofstrategiestocounteractthepotential problemof‘runningout’ofsusceptibleindividuals,such as:(i)ahighmutationratethatresultsinongoingimmune selection of antigenic variants (e.g. influenza virus), (ii) infection of mucosal surfaces, where it is difficult to induce long lasting protective immunity, resulting in repeated infections with thesame virus(e.g.respiratory syncytial virus) or (iii) infection of multiple species, therebyincreasingthenumbersofsusceptible individu-als.Asanadditionalstrategysomeviruses,suchas hepa-titisCvirus(HCV)andBornadiseasevirus(BDV),have evolved specific mechanisms thatlead to the establish-mentofpersistentinfectionsinatleastsomeindividuals whocanthenactasreservoirsfortheviruswithinahost population.
Inaprototypicalresponsetoanacuteviralinfectionitis expected that a virus will be cleared by innate and adaptiveimmuneresponseswithinafewweeksof infec-tion. Therefore, any infection that persists longer than thismaybeconsideredpersistent,evenifitdoesnotlead to life-long infection with the production of infectious virus.Indeed,forfootandmouthdiseasevirus(FMDV), cattle are considered persistently infected if infectious viruscanbedetectedformorethan28daysafterinfection [3,4].Notallpersistentinfectionsmayrepresenta selec-tive advantagefor avirus.Thus viruses,or viruseswith defective genomes, maypersist andslowly spread from cell to cell without the production of infectious virus. Such infections may nevertheless have important con-sequencesforthehostinthattheymayleadtochronicor evenfataldiseaseoutcomes,forexamplepersistent mea-sles virus (MeV) infections of the brain can lead to subacutesclerosingpanencephalitis(SSPE)[5,6],orthey mayinducelife-longimmunitytherebypreventing reoc-currenceoftheacuteinfection,ashasbeensuggestedfor MeV[7].Itisthisbroaddefinitionofpersistencethatwe
$Thisopinionpiecetakesitstitlefromaconferencewiththesame
willuseinthisopinionpieceasweconsidersomeofthe outstanding issues regarding ‘Within host RNA virus persistence’.
Epidemiologicalconsequencesofpersistentinfections
TheabilityofsomeRNAviruses,forexampleHCVand BDV, to establish persistent infections in a significant proportion of infected hosts is critical for them to be maintained within their host communities. However, theimportanceof persistentinfectionsfor the epidemi-ologyofotherviruseshasyettobeestablished(Table1), particularlythosethatcauseacuteinfectionswithobvious clinical outcomes. However, the example of FMDV is instructive.Although FMDVis best known for causing devastating outbreaks of acute disease in domesticated ungulates (e.g. cows and sheep), it can also establish persistent infections in some animals (persistently infectedsheepandgoatscanshedvirusforupto9months, cattleforupto2.5yearsandbuffalofor>5years)which canact as asourceof FMDVin future outbreaks [3,4].
Similarly, swine vesicular disease virus may be able establish persistent infections in pigs (>100 days) that mayactascarriersofswinevesiculardisease[8].Thereis also evidence that acute respiratory viruses, such as rhinoviruses [9,10] and respiratory paramyxoviruses [11],establish persistent infections in some individuals with production of infectious virus for many weeks or months, although such infections are often, but not always,associatedwithimmunedysfunction(seebelow) and/or age. Also, whilst many arboviruses are able to establishinapparentlife-longpersistenceintheir arthro-podvector[12],theyoftencausesignificantacutedisease intheirvertebratehosts,althoughtheirabilitytoestablish persistence in vertebrates may have been under-esti-mated[13].
Evensuchobviouslyacutevirusinfections suchas Zika virusandEbolavirusinhumanscanpersistinverysmall numbers of individuals over a period of months, and perhapsyears,andsuchpersistentlyinfectedindividuals
Table 1
Examplesofvirusesthatcanestablishpersistentinfections,includinginimmunocompromisedhosts,andsomeassociatedreferences
Arenaviridae,
Mammarenaviruses,forexamplelymphocyticchoriomeningitisvirus[81] Arteriviruses,forexampleequinearteritisvirus,simianhaemorrhagicfevervirus[82]
Bornaviridae,forexampleBornadiseasevirus[83] Bunyaviridae
Hantaviruses[37,38,84] Caliciviridae
Noroviruses,forexampleNorwalkvirus[85] Coronaviridae,forexamplemousehepatitisvirus[86] EndornaviridaeandPartiviridae;[87]
Filoviridae,
Ebolaviruses,forexampleEbolavirus[20,68] Marburgviruses,forexampleMarburgvirus[88] Flaviviridae
Hepacivuses,forexamplehepatitisCvirus[89] Pegivirus,forexampleGBviruses[90]
Flavivirus,forexampleWestNilevirus[91],Zika[15,67],Japaneseencephalitisvirus[92],tickborneencephalitisvirus[93] Pestiviruses,forexampleBovineviraldiarrhoeavirus[70,94,95]
Nodaviridae,forexampleflockhousevirusofinsects[35,96] Orthomyxoviridae,forexampleinfluenzaviruses[97,98] Paramyxoviridae[11]
Morbilliviruses,forexamplemeaslesvirus[99],caninedistempervirus[100],felinemorbillivirus[101,102] Respiroviruses,forexampleparainfluenzavirustype3[103]
Rubulaviruses,forexampleparainfluenzavirustype5[104],porcinerubulavirus[105] Picornaviridae
Aphthoviruses,forexamplefoot-and-mouthdiseasevirus[4]
Cardioviruses,forexampleTheilersmurineencephalomyelitisvirus[106]
Enteroviruses,forexamplepoliovirus[62],coxsackievirus[31],rhinoviruses[9,10],swinevesiculardiseasevirus[8] Pneumoviridae,forexamplerespiratorysyncytialvirus[107–109]
Reoviridae
Orbivirus,forexamplebluetonguevirus[21–23] Phytoreovirus,forexamplericegalldwarfvirus[34] Rhabdoviridae
Lyssaviruses,forexamplerabiesvirus[110,111] Togaviridae
can occasionally transmit the virus, thereby being a potential source of future outbreaks [14,15]. Whilst no one would suggest that the ability of Ebola virus to establish persistent infections has evolved in humans, the fact that even small numbers of individuals can become persistently infected may reflect its intrinsic abilityto establishpersistenceinitsnatural host.
One potential advantage of persistent infection for the infected host may be the maturation of the antiviral immune response anddevelopment of long-lasting pro-tective immunity. For instance, persistence of measles virus RNA and protein in lymphoid tissue for months aftertheprimaryinfectionstimulatescontinued produc-tionofplasmablastsproducingMeV-specificantibodyof increasing avidity, Tcells of evolvingfunctionality and the establishment of life-long immunity that charac-terizes recoveryfrom measles [16,17]. Thus,there may beclearadvantagesbothforthevirusandhostinevolving towardstheestablishmentofpersistentinfections, espe-ciallybecausevirus:hostinteractionsthatresultin persis-tentinfectionsareunlikely,inmostcases,toleadtohigh levelsof mortality.
Disease
consequences
of
persistence
AlthoughmostpersistentRNAvirusinfectionsare prob-ablyinapparent,persistentinfectionscansometimeslead to chronic disease or relapses of acute disease. Long-recognized examples include hepatocellular carcinoma andliverfibrosisasalateconsequenceofHCVinfection [18],andSSPEfollowingmeaslesvirusinfection.Indeed, the CNS, as an immunologically privileged site (see below), is an organ in which RNA viruses can often establishpersistentinfectionswithdiseaseconsequences [5,19]. Recent examples include reactivation of CNS infectionafterapparentrecoveryfromEbolavirusdisease [14,20]. Other chronic human diseases have also been linkedto persistent RNAvirusinfections,some contro-versially,includingPaget’sbonedisease,multiple sclero-sis, otosclerosis, post-polio syndrome and other late neurodegenerative diseases, chronic fatigue syndrome, certainautoimmunediseasesandexacerbationofchronic obstructivepulmonarydisease(Table2).
The mechanisms bywhich persistentRNA virus infec-tionsinducechronicdiseaseispoorlyunderstood,but it hasbeensuggestedthatchronicstimulationof inflamma-toryresponsesmaybeanimportantdrivingfactor(seeM. K. McCarthyandT. E.Morrison, PersistentRNAvirus infections:doPAMPsdrivechronicdisease,inthisissue of CurrentOpinionsinVirology).
Mechanisms
of
persistence
To establishpersistentinfections virusesmust (i) avoid eliminationbythehost’simmuneresponse,and(ii)avoid killingallinfectedcellswhilstmaintainingtheirgenomes withinsomeinfectedcells.Thismayentaillowlevelvirus
replication within cells that themselves remain persis-tently infected (e.g.BDV),infections in whichthevirus slowly spreads from cell to cell, but during which the infected cellsmaydie(e.g.rabies virus),or infectionsin whichtheviruspassivelyhideswithoutapparent replica-tion(e.g.BTVinerythrocytes[21–23]).Bothviralandhost factors will influence the type of persistent infection established. For viruses that clearly need to establish persistent infections to survive in nature themolecular basis bywhich they doso must bean evolvedprocess. However,thisisunlikelytobethecaseforviruseswhere theestablishmentofpersistencehasnoobviousselective advantageforthevirus,unlessthegeneralwaythevirus replicatesreflectstheneedofanancestralvirusto estab-lish persistentinfections,orthevirusestablishes advan-tageouspersistent infectionsin adifferenthost.
Repressionofvirustranscriptionandreplication
If a cell continues to synthesize high levels of viral proteins, the cell will probably die either as a direct consequence of virus replication or be eliminated by innate and adaptive immune responses. Therefore, to establishpersistent infectionsvirusreplicationprobably needs to be repressed in at least some infected cells. Long-lived cellssuchascardiacmyocytesandbrainand spinal cordneuronsmaybeparticularlylikelyto restrict virusreplicationandavoidimmune-mediatedelimination (seebelow).However,RNAvirusescanestablish persis-tentinfectionsinavarietyoftissues,notallofwhichare immune privilegedsites. Howrepressionof virus repli-cationisachievedinthesecells,evenforawell-studied virussuchasHCV,isusuallynotclear.HCVappearsto haveevolvedmechanismstohijackcellularfactors,such as microRNAs that bind its genome to protect it from degradation by the 50–30 exoribonuclease Xrn1 [24], inhibit its detection by sensors of the innate immune response and to regulate virus transcription,replication and genomic RNA abundance [25]. BDV, linked to
Table2
Examples of human diseases associated, sometimes controver-sially,withpersistentRNAvirusinfectionsandsomeassociated references
Autoimmunediseases:variousviruses[114,115] Chronicfatiguesyndrome:enteroviruses[116]
Exacerbationofchronicobstructivepulmonarydisease:Respiratory syncytialvirus[108]
Livercirrhosis/cancer;hepatitisCvirus[117]
Multiplesclerosis:anumberofRNAandDNAviruses[118,119] Paget’sbonedisease:Measlesandotherparamyxoviruses[11,120] Persistentarthralgia:Chikungunyavirus[121]
Post-poliosyndrome:poliovirus[122]
Progressiverubellapanencephalitis;Rubella[113] Subacutesclerosispanencephalitisandmeaslesinclusion
encephalitis:measlesvirus[123]
neurobehavioral disorders, is the only member of the order Mononegavirales that replicates in the nucleus andnon-cytolyticallyinfects animalsto establish persis-tence [26]. To maintain persistence, BDV tethers its genometohostcellchromosomes,sothatbothdaughter cellsremaininfectedwhenthecelldivides[27].BDValso blocksapoptosis,andthuspromotespersistence by pre-venting cell death, through the action of its accessory proteinX [28], which may influence theestablishment andreactivation ofBDV throughitsregulatoryfunction onviruspolymeraseactivity[29].Furthermore,50 -termi-nal trimming, a mechanism that leads to the loss of terminalnucleotidesfromtheBDVgenome,may atten-uate virus replication and transcription (thereby also helping to facilitate virus persistence), and preventthe genomefromactivatinginnateimmuneresponses,which also strongly influence the outcome of virus infections (see below) [30]. Similar modifications (deletions and insertions) at the 50 and/or 30 ends of the genomes of other RNA viruses,including LCMV, hantaviruses and coxsackieviruses [31–33], mayalso play similar roles in influencingtheirabilitytoestablishpersistentinfections. Certain insect and plant viruses also appear to have evolvedmechanisms,dependentupontheinsectsiRNA defense system, to dampen down their replication therebyfacilitatingviruspersistence.Here,viraldsRNA producedduringvirusreplicationisrecognizedby Dicer-2 (DCR2),acentral component of thesiRNApathway, thatprocessestheRNAtoproducevirus-derivedsiRNAs. ThesearesubsequentlyrecognizedbytheRNA-induced silencingcomplex(RISC)resultinginthespecific cleav-ageofviralmRNA,therebyinhibitinglethal,acute infec-tionsandpermittingviruspersistenceintheinsectvector [34,35].ThesiRNAdefensesystemmayalsosuppressthe replication of mammalian arboviruses in their insect vectorsto levelsthatfavourtheestablishmentof persis-tenceandthesurvivalofthevector[36].However,itis notknown whether other RNA viruses,such as certain paramyxoviruses,thatcanestablishpersistentinfections havealsoevolvedspecificmechanismstodownregulate virus transcription and replication under certain condi-tions.Nevertheless,itisinterestingtospeculatethatthe reason some viruses can establish persistence in their natural hosts but cause serious diseasein other species (e.g.hantaviruses[37,38],orpossiblyevenEbolavirus),is becausethemechanisms they haveevolved to dampen replicationintheirnaturalhostsdonotfunctioninother species.
Itisunlikelythathighlycytocidalviruseswillbeableto establishpersistentinfectionsunlesseithersomeinfected cells arerestrictive or semi-permissivefor virus replica-tion, or virus variants, including temperature sensitive mutants [39], with reduced cytopathogenicity are selected during the establishment of persistent infec-tions. Such an outcome is much more likely for RNA virusesthanDNAvirusesgiventhehighmutationrateof
RNAvirusesandtheirquasispeciesnature[40–43]. Simi-larly, thepresence and amplification of defective inter-fering particles may also dampen virus replication and thusinfluencetheestablishmentofpersistence[44–46].A rare way to establish RNA virus persistence, that is unlikely to be of evolutionary benefit to the virus, is the production of a cDNA copy of the viral RNA by endogenous reverse transcriptase, as has occurred for BDV and been proposed for measles virus and LCMV [47–50].
One general way for viruses to restrict replication is through limited activation of the interferon (IFN) response.IFNsarecellularfactorsproducedbyinfected cells that interact with receptors on infected and unin-fectedcellstoinduceexpressionofantiviralproteinsthat restrictvirus replication.This isan extremely powerful antiviralresponsethathasco-evolvedbetweenvirusand hostfor millionsof yearsandisaprogrammedresponse that plays an essential role in controlling many virus infections.Regulationofthisinnateresponseplaysarole inpersistenthepatitisAinfectionofhepatocytes[51]and arbovirusinfectionofmatureneurons[52].Thereisalso evidencethat,forsomeviruses,variantsthatinduceIFN, orarerelativelysensitivetoIFN,maybebetterablethan the wild type viruses to establish persistent infections [53,54].
Interactionwiththeimmunesystem
To establishpersistent infections inimmunocompetent individuals, viruses must avoid elimination by a fully functionalimmunesystem,includinginnateandadaptive responses. Withregardsinnateresponses,theseinclude avoidance ofelimination byapoptosis[63]and theIFN response.Indeed,tosurviveinnatureallvirusesmustat leastpartiallycircumventtheIFNresponseandtodoso theyoftenhide,ormodifytheirgenomes,suchthatthey donotactivatetheIFNsystem,and/orproduceproteins that act as IFN antagonists [64]. The mechanisms by which these IFN antagonists work potentially have a strong influence on the ability of viruses to establish persistent infections. Some lytic viruses (e.g. alpha-viruses in vertebrate hosts) block the IFN response byinhibitingcellulartranscriptionorproteinsynthesis, which inevitably leads to cell death. Therefore, for reasons discussed above, it is likely that non-cytolytic variants willevolve duringtheestablishmentof persis-tent infections. Other RNA viruses by nature are less lytic, andproduce IFNantagonists that allow cell sur-vival and promote the establishment of virus persis-tence. Indeed, the mechanisms ofaction of such viral IFNantagonistsmayhavespecificallyevolvedto facili-tatepersistence.
Toestablishpersistencevirusesmustalsoavoid elimina-tion by antibody and T-cell responses, and this may necessitatethedown-regulationofvirusproteinsynthesis and replication (see above). Viruses mayalso establish persistent infection in immunologically privileged sites suchasthebrainortestis[5,65,66]and,althoughthebrain is likely to be a dead-end organ for the most viruses, testicular infections can facilitate transmission [66–69]. The likelihoodof persistencecanalsobeinfluencedby the promptness of the virus-specific antibody response and relativetimingof the appearanceof populationsof effector and regulatory T cells. Viruses may be more likely to persist if the effector response is suppressed priortoclearanceorifinfectionoccursataveryyoungage andimmunologicdysfunction/toleranceisestablished(e. g.bovineviraldiarrhoeavirusinfectionincattle, congeni-tal rubellain humans, LCMVin mice)[70–72].Viruses canalso suppressdevelopmentof theadaptiveantiviral immuneresponseandpromotepersistencebyreplicating in cells and tissues of the immune system [73,74].For instance, bluetonguevirus,anarthropod-bornereovirus, infectsanddestroysfolliculardendriticcellsingerminal centres of lymph nodes and prevents prompt develop-ment of antibody capable of clearing infection [75]. Converselyithasalsobeensuggestedthatan inappropri-ate antibody responsemayfacilitate persistence, as has been suggested for MeV and Junin virus infections [76,77]. How this may work is an open question, but antibody-induced antigenic modulation can reduce the level of measles viral glycoproteins on the surface of persistently infected cells below that required for lysis by antibody-dependent cellular cytotoxicity (ADCC), a
mechanism by which specific immune cells, including naturalkillercellsandmacrophages,targetvirus-infected cells [78]. Furthermore, antibodies against the measles virus haemagglutinin canalso reduce the expression of viralproteinswithincells,therebypotentiallypreventing celldeathandreducingthelikelihoodofthecellsbeing killedbytheimmune response[79,80].
Toconclude,despitethefactthatpersistentRNAvirus infectionscanhaveimportantconsequencesbothforthe virusandhost,muchhasstilltobelearnedabout‘Within hostpersistentRNAvirus’infections.Withtheadventof new technologies, such as next generation sequencing, the tools are now available to better study persistent infections both in vivo and in vitro. Such studies may beusedtoinvestigatepossibleassociationsofpersistent virus infections with chronic human diseases. A better understanding oftheincidence andnatureofpersistent RNAvirusinfectionsmayalsopromotedevelopmentof bettermethodsforsurveillanceandcontrol;forexample, it may be possible to design improved vaccines using viruses that establish persistent infections as vectors to inducelong lastingimmunity.
Acknowledgments
RERisfundedbytheWellcomeTrust,UK(Grant101788/Z/13/Z)and DEGbyUSNationalInstitutesofHealth(R01NS038932).TheUniversity of St Andrews is a charity registered in Scotland (SC013532).
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