Type I Interferon at the Interface of Antiviral Immunity and Immune Regulation: The Curious Case of

21 Pages·2015·1.41 MB·English

HindawiPublishingCorporation
Scientifica
Volume2013,ArticleID580968,20pages
http://dx.doi.org/10.1155/2013/580968
Review Article
Type I Interferon at the Interface of Antiviral Immunity and
Immune Regulation: The Curious Case of HIV-1
AdrianoBoasso
ImmunologySection,ChelseaandWestminsterHospital,369FulhamRoad,LondonSW109NH,UK
CorrespondenceshouldbeaddressedtoAdrianoBoasso;[email protected]
Received12November2013;Accepted10December2013
AcademicEditors:G.ChenandM.Clementi
Copyright©2013AdrianoBoasso.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,
whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
TypeIinterferon(IFN-I)playacriticalroleintheinnateimmuneresponseagainstviralinfections.Theyactivelyparticipateinanti-
viralimmunitybyinducingmolecularmechanismsofviralrestrictionandbylimitingthespreadoftheinfection,buttheyalso
orchestratetheinitialphasesoftheadaptiveimmuneresponseandinfluencethequalityofTcellimmunity.Duringinfection
withthehumanimmunodeficiencyvirustype1(HIV-1),theproductionofandresponsetoIFN-Imaybeseverelyalteredbythe
lymphotropicnatureofthevirus.InthisreviewIconsiderthedifferentaspectsofvirussensing,IFN-Iproduction,signalling,and
effectsontargetcells,withaparticularfocusonthealterationsobservedfollowingHIV-1infection.
1.Introduction Infection by the human immunodeficiency virus type 1
(HIV-1) may represent an extreme example of how chronic
Interferons(IFN)areaheterogeneousclassofsolubleimm-
IFN-Iproductionprogressivelyunderminesthedevelopment
unemediatorswhichwereoriginallydefinedbytheirability
ofefficientlong-termantiviralimmunity[9,10].
tointerferewiththereplicationofdiversetypesofvirusesin
vitroandinvivo.HumantypeIIFN(IFN-I)includeIFN-𝛼 Different cells have the potential to produce IFN-I and
(14 genes, resulting in more than 22 products) and IFN-𝛽, themechanismbywhichviralinsultsaresensedvariesdepe-
bothencodedbygenesclusteredonchromosome9,probably ndingonthecelltype,asdoesthepotencyoftheIFN-I-pro-
generatedasaresultofgeneduplicationevents,asepitomized ducing response. In the case of HIV-1, most studies have
by the presence of multiple pseudogenes [1]. IFN-𝜀, IFN-𝜅, focussedonplasmacytoiddendriticcells(pDC)asthemain
IFN-𝜏,andIFN-𝜔havealsobeendescribedinmammalsas producersofIFN-Ifollowingviralexposure[9,11,12].How-
membersoftheIFN-Ifamily.Thisreviewisfocusedonthe ever,recentevidenceindicatesthatthesourceanddynamics
literaturecoveringtheregulationandthefunctionofIFN-𝛼 of IFN-I production may change during the course of infe-
andIFN-𝛽. ction, and pDC may be replaced by myeloid dendritic cells
IFN-Iareproducedinlargequantitiesinresponsetoviral (mDC) and monocytes/macrophages as the main source of
infectionsandaregenerallyregardedasakeybridgingmech- IFN-Iduringthetransitionfromacutetochronicinfection
anismbetweeninnateandadaptiveimmuneresponses,exert- [13].
ingbothantiviralactivity,andimmunostimulatoryfunctions, Basedonthemolecularmechanismsofviralsensinginvo-
such as promoting antigen-presenting cell maturation and lvedinHIV-1recognitionbydifferentcells(1),theevidence
moldingThelpercellresponses[2–8].However,thenotion availableonIFN-Iproductionbydifferentcelltypesduring
that IFN-I serve only as effector immune mechanisms may theacuteandchronicphasesofinfection(2)andthecombi-
need to be revised based on accumulating evidence which nationofantiviralandimmunomodulatoryactivityofIFN-I
highlightsthepotentimmunoregulatoryabilityofthesemol- (3),itispossibletospeculatethatIFN-Imayservedifferent
ecules.Duringchronicviralinfections,thebeneficialantivi- purposes during different stages of chronic infections, and
ralandimmunostimulatoryeffectsofIFN-Imaybeoverruled that the dysregulation of IFN-I production during HIV-
bytheprolongedstimulationofIFN-I-inducedcytostaticand 1 infection may contribute to progressive immunodefici-
proapoptoticmechanisms. ency.
2 Scientifica
2.ViralSensingby activation of phosphatidylinositol 3-kinase (PI3K)-𝛿 [31].
PatternRecognitionReceptors IFN-𝛼/𝛽 secreted during this early phase may act in an
autocrine manner through the dimeric type I IFN receptor
Innatesensingofvirus-relatedpathogenassociatedmolecu- (IFNAR)andstimulatedenovoproductionofIRF7,further
larpatterns(PAMP)reliesprimarilyonrecognitionofviral stimulating IFN-I secretion in a potent positive feedback
nucleic acids by toll-like receptors (TLR) in the endosomes loop of IFN-I production [28]. The IRF7-mediated signall-
ofspecialisedimmunecells,orbycytoplasmicsensorswidely ingpathwayisthereforeresponsibleforthedifferentiationof
expressedbydifferentcelltypesandnotrestrictedtoimmune pDC into efficient IFN-I producing cells (IPC). PI3K and
cells[14–19]. IRF7signallingisnotrequiredfortheproductionoftumor
HIV-1 interacts with and infects cells expressing CD4, necrosis factor (TNF)-𝛼, interleukin (IL)-6, and the che-
which is engaged by the viral envelope glycoprotein gp120. mokines CXCL10 and CCL3, which rely on the canonical
Thus,IFN-IproductionduringHIV-1infectionismainlysus- nuclear factor (NF)-𝜅B pathway (Rel-A: p50 dimer) which
tainedbyimmunecellswhichareeitherexposedtoorinfe- inturnrequiresmitogen-activatedproteinkinasep38(p38-
ctedbyHIV-1. MAPK) activity [32]. The same pathway is responsible for
promoting the expression of the costimulatory molecules
2.1. Toll Like Receptors. Toll-like receptors are a family of CD80 and CD86, which are conditions necessary for the
patternrecognitionreceptors(PRR)preferentiallyexpressed maturationofpDCintofullycompetentantigenpresenting
by cells which participate in the innate immune responses cells(APC)[32].TLR7/9engagementalsopromotesupregu-
against invading pathogens [14–16]. At least four TLR have lation of the immunoregulatory enzyme indoleamine (2,3)-
thepotentialtosenseviralnucleicacidsinhumans.Signalling dioxygenase (IDO) in both murine and human pDC [33–
viaTLR3,TLR7,andTLR8istriggeredbyviralRNA,whereas 36]. In murine models, IDO regulation via TLR7/9 occurs
TLR9 recognizes unmethylated CpG-rich DNA sequences following activation of the noncanonical NF-𝜅B pathway
[15, 20]. Although RNA-sensing TLR have the potential to (Rel-B:p52complex)[37],andnon-canonicalNF-𝜅Bisalso
recognizeHIV-1,onlyTLR7-expressingpDCappeartorespo- requiredtosupportIFN-𝛼production[38].
ndpromptlytoviralexposure.Conversely,theavailableevi- IRF7andNF-𝜅Barenotsimultaneouslyactivatedfollow-
denceeitherexcludesorisinconclusiveregardingtheability ingTLR7/9engagement,andthepathwaywhichdominates
ofHIV-1todirectlyactivatecellsexpressingTLR8orTLR3, the signalling cascade is determined by the intracellular
such as mDC and MΦ, but also microglia and astrocytes compartmentwhereTLR7/9engagementoccurs[39].
withinthecentralnervoussystem[12,21–23].
TheabilityofpDCtorespondtoHIV-1stimulationappe- 2.2.CytoplasmicRNASensors. TLRrepresentpowerfulmec-
arstobemainlydependentonTLR7signalling[24],although hanismsforviralrecognition,buttheirexpressionislimited
aroleforTLR9cannotbeexcluded[12].TheHIV-1viralcycle to immune cells and the restriction to endosomal comp-
includes the formation of a DNA/RNA heterodimer and a artment prevents them from detecting viruses which have
doublestrandedDNAproviralDNA,whichrepresentpote- reached the cytoplasmic environment. Retinoic acid-indu-
ntial ligands for TLR9 via CpG-rich DNA regions. Partial ciblegene1(RIG-I)-likereceptors(RLR)areafamilyofPRR
reverse transcription may occur already in the virion, due broadly expressed among different human cells, and confer
tothepackagingofcomplexesformedbyreversetranscrip- the ability to sense virus-derived RNA within the cytopl-
tase, viral RNA genome and transfer RNA primer [25–27]. asm [15, 17, 18]. RLR include RIG-I, melanoma differentia-
However, the reverse transcription process is completed in tion factor (MDA)5, and laboratory of genetics and phys-
thecytoplasmicenvironment[25,27],secludedfromendo- iology(LGP)2protein,allofwhicharepotentlyupregulated
somal TLR9. Whether fragment of DNA of viral origin by IFN-I [40]. Studies conducted in transgenic mice sug-
includedinthevirionengulfedbypDCandprocessedviathe gest that different RLR are critical in the recognition of
endosomal pathway can trigger TLR9-mediated responses and IFN-I response against different viruses [18]. How-
remainsuntested. ever, it remains unclear how RLR distinguish viral RNA
Engagement of TLR7/9 results in the activation of a from cellular RNA, and therefore trigger IFN-I produc-
complex network of transduction signalling pathways in tion only in infected cells. The specificity for exogenous
pDC.ThefirststeprequiredforTLR7/9signaltransduction RNA may be dependent on the recognition of second-
istherecruitmentoftheadaptormoleculemyeloiddifferen- ary structures which are common in viral RNA genomes
tiation primary-response gene 88 (MyD88), which in turn [18]. RLR signal transduction occurs through binding of
associates with other adaptor and signalling molecules to the receptor to the mitochondrial adaptor IFN-𝛽 prom-
formacomplexcomprisedofTNF-receptor-associatedfactor oter stimulator (IPS)-1 and formation of a signalling com-
(TRAF)6, Bruton’s tyrosine kinase (BTK), IL-1R-associated plex leading to the activation of the kinases TNF rece-
kinase(IRAK)4andIRAK1[20,28,29].Thesignallingcom- ptor-associated factor (TRAF)-associated NF-𝜅B actvator
plex catalyzes the activation of different intracellular path- (TANK)bindingkinase(TBK)1-IK𝛽kinase(IKK)𝜀[40].The
ways. TBK1-IKK𝜀isthenresponsibleforbothIFN-Iproductionvia
Thepathwaymediatedbytheinterferonregulatoryfactor IRF3andIRF7andforNF-kBactivation[40].
(IRF)7 is directly associated with activation of IFN-𝛼 and Berg and colleagues demonstrated that genomic HIV
IFN-𝛽 genes following nuclear translocation of IRF7 [30]. RNAcantriggerinflammatoryresponsesinhumanperiph-
Signalling through the IRF7 pathway is dependent on the eralbloodmononuclearcells(PBMC)viaRIG-Irecognition,
Scientifica 3
leading to production of the interleukin (IL)-6, TNF-𝛼, Upon TLR7/9 engagement, pDC can mature into antigen-
IFN-𝛼,andIFN-𝛽[41].Thecellularsourcesoftheproinflam- presenting cells (APC) or IFN-I-producing cells (IPC), and
matory cytokines were not investigated in this study. It theprevalenceofonepathwayovertheotherlargelydepends
is plausible that, during HIV-1 infection in vivo, all cells ontheintracellularlocaleinwhichtheTLRligandtriggersits
susceptible of infection have the potential to respond to receptor[23,39].Thus,theengagementofTLR7/9withinthe
HIV-1genomicRNAviaRIG-Isensing.However,thenature earlyendosomescausesstrongactivationoftheIRF7pathway
of the responses may differ depending on the target cells, viaanIFN-𝛼/𝛽-dependentpositivefeedback,resultinginthe
andinflammatoryresponsesmaybedifferentiallymediated production of high quantities of IFN-𝛼 and pDC differen-
by DC and monocyte/macrophages compared to CD4 T tiationintoIFN-I-producingcells(IPC)[39].Conversely,if
lymphocytes. the TLR ligand is trafficked to the lysosomes or late endo-
somes,signaltransductionviatheNF-𝜅Bpathwayisfavored,
resultingintheupregulationofcostimulatorymoleculesand
2.3. Cytoplasmic DNA Sensors. The presence of a RNA-
maturationintoAPC[39].O’Brienandcolleaguesreported
DNAhybridduringreversetranscriptionoftheHIV-1RNA
thatHIV-1ispreferentiallytraffickedtotheearlyendosomes
genomeintodsDNAsuggeststhatcytoplasmicrecognitionof
ofpDC,whichinturnpromotesapersistentlyactivatedIPC
the proviral DNA may occur before its translocation to the
status,combinedwithpartialorincompletematuration[23].
nucleusandintegrationintothehostgenome.
ThebindingoftheHIV-1envelopeglycoproteingp120to
The cytosol of eukaryotic cells is rich in enzymes with
CD4,butnottothecoreceptorsCCR5orCXCR4isrequired
DNase activity, which prevent accumulationof DNA in the
forvirionengulfmentandsubsequentactivationofpDCvia
cytoplasm [42]. However, when the preventive measures
TLR7 engagement [12, 55]. The interaction between gp120
exerted by cytoplasmic DNases fail, DNA of viral origin
and CD4 is stabilized by accessory interactions involving
may accumulate in the cytoplasm. Double stranded DNA
cellularadhesionmoleculesonboththecellmembraneand
is a potent immune stimulator when present in the cytosol
viral envelope, allowing the formation of a stable binding
of target cells [43, 44], and recent evidence indicates that
interface between HIV-1 and the target cells [56–58]. Thus,
single-stranded DNA with specific signatures, such as AT-
the envelope of newly formed HIV-1 virions incorporates
richregions,isalsoastrongactivatorofimmuneresponses
cellular proteins derived from the host cell of origin [56,
[45].SensingofcytoplasmicDNAtriggersacascadeofsignal
57, 59]; these cell-derived proteins contribute to virus-cell
transductionorchestratedbytheadaptormoleculestimulator
interactions and may modulate the dynamics of infection
ofinterferongenes(STING)[46–49],leadingtotheproduc-
of target cells and uptake by endocytotic cells [57–60]. In
tion of proinflammatory and antiviral cytokines, including
addition,theHIV-1envelopeisnothomogenous,butrather
IFN-I [48]. STING engages TBK1 to cause IRF3 activation,
organized in a functional substructure enriched in tightly
andtheSTING-TBK1-IRF3signalingaxisiscriticalforIFN-I
packed cholesterol, similar to the lipid rafts described in
inductionbycytosolicDNA[50].
eukaryoticcells,includinghumanleukocytes[9,60,61].The
Recent evidence indicates that cytosolic HIV-1-derived
organization of a functional virion-associated lipid raft is
dsDNAorRNA/DNAheterodimersmaytriggerinnateimm-
required to confer HIV-1 the ability to induce potent IFN-I
uneresponses.Gaoandcolleagueshaveusedboththemono-
production via pDC stimulation [9]. Thus, the efficiency of
cyticcell lineTHP1 and primaryhuman monocyte-derived
HIV-1 uptake by pDC and the potency of IFN-I induction
macrophagesanddendriticcellstoshowthatHIVinfection
are strongly reduced if envelope-associated cholesterol is
inducestheproductionofcyclicguanosinemonophosphate-
withdrawn by chemical treatment [9]. However, cholesterol
adenosine monophosphate (cGAMP), which binds to and
depletedHIV-1partiallyretainstheabilitytopromotepDC
activates STING resulting in the production of IFN-I [51].
TheproductionofIFN-𝛽wasstrictlydependent onreverse maturationintoAPC[9],suggestingthattheintegrityofthe
virion-associatedlipidraftmaynotonlyreducetheefficiency
transcription, indicating that HIV-1 DNA acts as the initial
of HIV-1 uptake, but also modify the dynamics of HIV-1
triggerforIFN-Iproduction[51].Furthermore,Jakobsenand
traffickingandsubsequentTLRsignallinginfavourNF-𝜅B-
colleagues have shown that ssDNA generated from HIV-1
mediatedAPCmaturationratherthanIRF7-dependentIFN-
proviral genome is a potent activator of IFN-I in primary
𝛼production.
humanmonocyte-derivedmacrophages[52].Singlestranded
ActivationofpDCmayoccurwithinhoursfromexposure
HIV-1DNAengagestheIFN-inducibleprotein16(IFI16)in
to HIV-1 in vivo. Intravaginal infection of rhesus macaques
thecytoplasmofmacrophages,leadingtotheactivationofthe
causedrapidaccumulationofactivatedpDCatthemucosal
STING-TBK1-IRF3pathway[52].
siteofinfection,whichresultedinmacrophageinflammatory
protein (MIP)-3𝛼-mediated chemoattraction and infection
3.CellularSourcesofIFN-Iduring ofCCR5-expressingCD4Tcells,contributingtothespread
HIV-1Infection oftheinfectiontosecondarylymphoidtissues[62].Lubong
Sabado and colleagues reported that pDC relocate to lym-
3.1. Plasmacytoid Dendritic Cells. Plasmacytoid DC are the phoidtissuesalreadyduringprimaryHIV-1infection,acon-
mostpotentproducersofIFN-Iinresponsetoviralinfections ditionwhichpersiststhroughoutthecourseofdisease[63].
[16,53,54].ExpressionofendosomalTLR7andTLR9allows However, reports on IFN-𝛼 secretion by pDC in lymphoid
pDC to respond to both RNA and DNA viruses which tissues during chronic HIV-1 infection showed contrasting
are engulfed and trafficked into the endosomal pathway. results. For example, although IFN-𝛼 and upregulation of
4 Scientifica
IFN-stimulatedgenes(ISG)hasbeenreportedintissuesfrom to a shift in the distribution of productively infected cells
HIV+patients[64,65],Nascimbeniandcolleaguesshowed amongdifferentcelltypes.Dendriticcellsmayactascatalysts
that pDC in the spleen of HIV-infected patients have an fortheinfectionofCD4Tcellsviacell-celltransfer[70,71],
immaturephenotypeanddonotcontributetotheincreased but activated CCR5+ CD4 T cells are the main target for
IFN-𝛼 production [66]. The state of partial or incomplete infectionandthemainsourceofviralreplicationthroughout
pDCmaturationisconfirmedinthestudybyBenlahrechand theacutephase[72,73].However,thenumberofCCR5+T
colleagues, who have recently shown that expression of the cells decreases progressively during acute infection both in
immunoglobulin-liketranscript(ILT)7,aregulatoryreceptor theperipheryandinlymphoidtissues,likelyduetoacom-
expressed by immature circulating pDC but not partially bination of viral cytotoxicity, activation-induced apoptosis
differentiatedcells[36],isreducedinpDCfromHIV-infected andimmune-dependentkillingmediatedbynewlyactivated
patientswhenviralreplicationisnotefficientlycontrolledby HIV-1-specificcytotoxicCD8Tlymphocytes(CTL)[72–74].
therapy[67]. Thus, as the pool of CCR5+ CD4 T cells decreases, CD4-
Recent evidence suggests that pDC may be the predo- expressing mDC and monocyte/macrophages may become
minant source of IFN-I only during the initial phases of increasinglymoreimportantastargetsforinfection,andther-
acute infection, whereas mDC and macrophages become eforemoresusceptibletoactivationviacytoplasmicRLR.
importantproducersofIFN-𝛼whenthecourseofinfection Thecriticalquestionsthatremainunanswerediswhether
transitions to the early chronic phase [13]. Both mDC and the prolonged IFN-I response observed during pathogenic
monocyte/macrophagesexpressTLR8,whichhasthepoten- HIV-1/SIVinfectionplaysadeterminantroleinviralimmu-
tialtorecognizeviralRNA[68,69].However,severalstudies nopathogenesisandwhetherpDC-mediatedacuteresponses
haveshownthatinvitromaturationofmDCandmonocytein or chronic IFN-I responses mediated by non-pDC subsets
presenceofHIV-1isabystandereffectoccurringinresponse are potentially valuable targets for immunotherapeutic or
tocytokinesproducedbyHIV-1-activatedpDC,suchasIFN- curativeinterventions.
𝛼 and TNF-𝛼 [12, 21–23]. In addition, even in conditions
in which TLR8 engagement occurs, mDC do not respond 3.3.OtherCellularSourcesofIFN-I. Thebroadexpressionof
by secreting IFN-I, but rather mature into interleukin (IL)- RLRandcytosolicDNAsensorsinnumerouscelltypesandin
12-secretingAPC[68,69].Thus,IFN-IproductionbymDC differenttissues[18]suggeststhatanycellsusceptibletoHIV-
andmacrophagesduringthepost-acuteandchronicphases 1 infection, and therefore to cytoplasmic exposure of viral
of HIV-1 infection may depend on molecular pathways RNA,hasthepotentialtosecreteIFN-𝛼duringHIV-1infec-
other than sensing of extracellular viral particles virus via tion.Nonetheless,evidenceaboutIFN-𝛼productionbycells
endosomalTLR. otherthanDCandmonocytesisscatteredandlargelyincon-
clusive about its relevance for systemic immune activation
3.2. Monocytes/Macrophages and Myeloid Dendritic Cells. and immunopathogenesis. However, IFN-𝛼-producing cell
Endosomal TLR allow recognition of nucleic acids from subsetswhichareconfidedtospecificanatomiclocationsmay
viruses engulfed by specialized cells, but may not sense contribute to inflammatory processes within non lymphoid
viral genomes which have gained access to the cytoplasm. tissues and organs, partially accounting for the develop-
Intracellular RLR and DNA sensors are triggered by viral mentofHIV-1-associatednon-communicablecomorbidities
genome in the cytoplasm and induce the production of (NCCM).Anincreasingbodyofevidencesuggestsacausative
antiviral and immunostimulatory cytokines, such as IFN-𝛼 linkbetweenchronicinflammationandsomemanifestations
and TNF-𝛼 [18]. RLR are expressed by most cell types and of NCCM. One example is that of neurological complica-
their triggering requires that the viral genome has reached tionsassociatedwithneuroinflammation,whichareobserved
thecytoplasm,aconditionwhichisalsonecessarytoachieve even in patients in whom viral replication in controlled by
productive infection of the target cell. Conversely, TLR7/9- combination antiretroviral therapy (cART) [75–77]. Thus,
mediated pDC responses would not be triggered during a microglialactivationandanIFN-drivengeneregulationsig-
productive infectious cycle, due to the segregation of the naturearecharacteristicofHIV-associatedneurologicalsym-
receptorsintheendosomalcompartment.Thismayrepresent ptoms,suchascognitiveimpairmentanddepressivedisorder
acriticaldifferencebetweenIFN-Iresponsesorchestratedby [75, 76, 78, 79]. It is noteworthy that neurologic disease
uninfectedpDCduringtheearlyphasesofviralexposureand associatedwithinfectionwithanotherhumanlymphotropic
IFN-Iproductionbyproductivelyinfectedcellsduringlater retrovirus, the human T-lymphotropic virus type 1 (HTLV-
stagesofinfection. 1), is also associated with an IFN-dominated inflamma-
This transition from a pDC-mediated to an apparen- tory profile. Thus, Tattermusch and colleagues described
tlypDC-independentIFN-Iresponsehasbeenrecentlydes- an IFN-inducible signature in HTLV-1-associated myelopa-
cribed in the HIV-1 simian model of simian immunodefi- thy/tropicalspasticparaparesis(HAM/TSP)[80,81].Itisstill
ciency infection (SIV) of Rhesus macaques by Kader and unclearwhetherperipheralsourcesofIFN-I,suchasDCor
colleagues [13]. Monocyte derived macrophages have been macrophagesarethesoleresponsiblefortheneuropathologic
shown to respond to HIV-1 proviral DNA via intracellular effectsorwhetherastrocytesandmicroglialcellsaredirectly
DNA sensors [51, 52], and genomic HIV-1 RNA activates involvedintheproductionofIFN-Iduringtheinflammatory
innateimmuneresponsesinperipheralmononuclearcellsvia response. Whether IFN-I production by these cells plays a
RLR[41].Thequestioncanberaisedastowhetherthemain rolealsointheimmunopathogenesisofHIV-1infectionisyet
source of IFN-I changes during HIV-1 infection in relation tobedetermined.
Scientifica 5
4.EffectofIFN-IonTargetCells promoter region of IFN-I-stimulated genes [99, 100]. Thus,
whileIFN-IcanactivategenescontainingeitherISREorGAS
TypeIIFNarethemostpotentnaturalmediatorsofantiviral promoterelements,IFN-𝛾isunabletoinducetheformation
activity in humans. The combination of proapoptotic and of ISGF3 and activate genes via ISRE [101]. Signalling via
cytostaticactivity,aswellasthedirectinductionofintracel- STAT1-STAT2isresponsibleforsomeofthemostcommonly
lularviralrestrictionfactorscontributetogenerateacellular observed effects of IFN-I during chronic HIV-1 infection,
environmentwhichisunsuitableforviralreplication[1,3,82, includingtheactivationofproapoptoticandcytostaticgenes,
83].ThereplicationofHIV-1isefficientlyinhibitedbyIFN- viralrestrictionfactorsandimmunomodulatoryeffects[102–
I in vitro, but the potential of IFN-I as antiretroviralagents 104].
duringchronicHIV-1infectioninvivoisdubious[84–89]. Type I IFN also triggers phosphorylation of STAT3
IFN-IalsocontributetothematurationofAPCandexert [105],promotingitsdimerizationandmigrationtothenucl-
a modulatory effect on different T cell subsets, therefore eus. STAT3 homodimers activate the transcription of genes
posingthefoundationsforpromotingantigen-specificadap- containing the enhancer sequence STAT3-binding element
tive immune responses and shaping them according to the (SBE).DespitesharinghighsequencesimilaritywithSTAT1,
invadingpathogen[1,6,7,53,82,90]. STAT3 activation induces a gene expression profile distinct
fromthatdependentonSTAT1-STAT2[106],includinggenes
4.1. IFN-𝛼 Receptor Complex and Signalling. The cellular of the B cell lymphoma (BCL) family and the oncogene
effectsofIFN-Iaremediatedbytheengagementofacommon MYC,whichpromoteproliferationandantagonizeapoptosis
receptor complex, the IFN-𝛼 receptor complex (IFNAR), [107, 108]. Furthermore, STAT3 is responsible for the sup-
whichisexpressedatdifferentlevelsonthesurfaceofvirtually pressionofinflammatoryresponsesviaIL-10,whichdirectly
allhumancells.TheIFNARcomplexisaheterodimerofthe counteractsSTAT1activity[109].
two subunits IFNAR1 and IFNAR2. Human IFNAR1 com- IFN-𝛽 also activates the signal transduction pathway
prisesanextracellulardomain,atransmembraneregionand mediated by JAK1 and phosphoinositide 3-kinase (PI3K),
an intracellular domain of 100 amino acid residues. Three leadingtotheexpressionofgenesregulatedbycyclicadeno-
different forms of IFNAR2 have been described: the full sinemonophosphate(cAMP)viathenucleartranslocationof
lengthreceptorchainwhichincludesa250residuescytoplas- cAMP-responsive-element (CRE) binding protein (CREB).
micportion,analternativeformwithashortedintracellular SimilartotheSTAT3-mediatedpathway,PI3Ksignallingcan
portion (67 residues) [91, 92] and a soluble form lacking also result in IL-10 production by DC [110]. However, the
the transmembrane and cytoplasmic portions [91]. Human twopahwaysappeartobeindependentfromeachother.The
IFNAR2 binds all human IFN-I with higher affinity than mammaliantargetofrapamycin(mTOR)isactivateddown-
IFNAR1,buttheaffinityoftheIFNARheterodimerformost stream of the PI3K signalling cascade [111]. Activation of
humanIFN-Iis10foldhigherthanIFNAR2alone[91,93,94]. mTOR is independent of STAT signalling and does not
The cytoplasmic domains of IFNAR1 and IFNAR2 are modify the gene expression profile, but modulates mRNA
associated with the tyrosine kinase (TYK)-2 and janus kin- translationbyregulatingtheactivationofp70S6kinaseand
ase (JAK)-1, respectively [91]. Upon IFN-I binding to the thephosphorylationoftheribosomalproteinS6[112,113].
IFNARcomplex,thetyrosinekinasesareactivatedandorc- The signalling pathway mediated by p38 mitogen-activ-
hestrate the signal transduction machinery [95]. TYK-2 ated protein kinases (p38-MAPK) and extracellular signal-
and JAK-1 phosphorylate tyrosine residues on the IFNAR, regulatedkinase(ERK)1orERK2isalsoactivatedbyIFN-I.
and phosphorylated tyrosines act as docking sites for the Thus,geneswhichcontainISREandGASelementsintheir
src-homology-2 (SH2) domains of signal transducer and promoterregioncanbeupregulatedviaaSTAT-independent
activator of transcription (STAT) proteins, which are then pathwaymediatedbyp38-MAPK[114–116],andthecytostatic
targetedforphosphorylation[96,97].STAT1,STAT2,STAT3, and antiviral effects of IFN-I are dependent on intact p38-
and STAT5 are expressed and activated by IFN-I in most MAPKsignallingmachinery[117–120].
cell types, whereas IFN-I-induced activation of STAT4 and It is reasonable to expect that different IFN-I signal
STAT6islimitedtolymphocytes[96,97]. transductionpathwaysareactivatedduringHIV-1infection.
STAT2 is recruited to the IFNAR1 cytoplasmic domain However, the STAT1-STAT2 pathway is arguably the best
andisphosphorylatedbyTYK-2,servingasalureforSTAT1 described in the setting of IFN-I production during HIV-
[98],whichisalsophosphorylatedattyrosine701.TheSTAT1- 1 infection. The activation of STAT proteins by HIV-1 was
STAT2heterodimerassociateswiththeDNAbindingprotein described in different experimental conditions involving
interferon regulatory factor 9 (IRF9) to form a signalling HIV-1-induced IFN-I production, productive HIV-1 infec-
complex called IFN-stimulated gene factor-3 (ISGF3). The tionoftargetcellsorsimpleexposuretoviralproteins.Thus,
ISGF3complextranslocatestothenucleuswhereitpromotes in vitro exposure of cell lines or primary leukocytes to
the transcription of IFN-I-stimulated genes (ISG) by inter- wholeHIV-1virionswasrepeatedlyshowntoactivateSTAT-
acting with the IFN-stimulated response elements (ISRE), dependentpathwaysinCD4Tcellsandcellsofthemonocytic
usually situated within 200 base pairs of the transcription lineage [55, 121, 122]. Interestingly, Renga and colleagues
start site. An additional phosphorilation of STAT1 at serine reportedthatexposureofmonocyticcelllinestotheHIV-1
727,mediatedbyproteinkinaseC-𝛿(PKC-𝛿),isessentialfor matrixproteinp17wassufficienttoactivatetheJAK1/STAT1
efficient transcriptional activity [1, 98]. In addition, STAT1 axis and cause upregulation of STAT1 sensitive genes [123],
homodimers can bind to IFN-𝛾-activated site (GAS) in the suggestingthatSTAT1activationduringHIV-1infectionmay
6 Scientifica
alsooccurindependentofIFN-Iproduction.Simianimmun- expression between different species translate into different
odeficiency virus (SIV) infection of nonhuman primates in transmission and disease progression phenotype [142, 145].
vivo resulted in upregulation of gene expression for STAT1, However,littleattentionhasbeengiventothepossibilitythat
STAT2andIRF9duringtheacutephaseofinfection,which differentprofilesofCCR5expressionamongprimatespecies
was protracted through the early chronic phase only in mayaccountfordifferentsensitivitytoIFN-Iproduction,and
disease susceptible primate species, not in disease resistant thereforedifferentpatternsofregulationofIFN-I-stimulated
Africanspecies[124,125].AlthoughsignallingviatheISGF3 genes during chronic HIV-1 or SIV infection, ultimately
complexisregulatedbypost-transcriptionalmodificationof accountingfordifferencesindiseasesusceptibility.
STAT proteins, not by modulation of STAT and IRF9 gene
expression,theobservedincreasesintheexpressionofthese
4.3.CytostaticandProapoptoticEffects. TypeIIFNarewidely
moleculesinSIV-infectedmacaques[124,125]isindicativeof
recognizedasthemostpotentnaturalmediatorsofantiviral
enhancedactivityoftheIFN-I/ISGF3axis.
activityinhumans[1,3].Becausethelifecycleofvirusesis
ThecentralroleplayedbyPI3Kinmultiplesignaltrans-
directlyinfluencedbytheintracellularenvironment,efficient
ductionpathwaysrendersitdifficulttodistinguishitspartici-
antiviralmechanismshavedevelopedtointerferewithbasic
pationinmediatingtheeffectsofIFN-Ifromotherbiochem-
cellular functions or, in an even more resolute manner,
ical, cellular and molecular events occurring during HIV-1
eliminate infected cells which represent the factories of
infection. The contribution of PI3K in neuroinflammation
viral replication. These goals are achieved by IFN-I via the
associatedwithHIV-1infectionhasbeendescribed[126–128],
upregulation of genes exerting cytostatic and proapoptotic
but the role of Pi3K/mTOR in HIV-1 immunopathogenesis
activities.Thebroadlyeffectiveantiviralmechanismsinclude
remainsunclear.
theinductionofmolecularmechanismsinterferingwithpro-
Activationofthep38-MAPKpathwayduringHIV-1infe-
teinsynthesisandcellularactivity,aswellasthestimulation
ctionhasbeendescribedbyseveralgroups[129–139].How-
ofligand/receptor-dependentapoptoticpathwaysandstress
ever,studiesonthep38-MAPK/ERKpathwayhavegenerally
responses.Whileexertingpotentantiretroviralactivity,these
focused on the direct effect of HIV-1 gp120 singalling via
mechanismsclearlyinterferewithbasiccellularfunctionsand
engagement of CD4 or the coreceptors CCR5 and CXCR4
carry a potentially destructive risk for the host, hence the
[129, 136–139], rather than IFN-I production. In particular,
needfortightregulationofboththekineticofactivationand
activationofp38-MAPK/ERKhasbeenstudiedinreference
therestrictiontospecificanatomicallocations.
toitsroleinmodulatingcellactivationandHIV-1replication
DuringHIV-1infection,thechronicinductionofIFN-I
[129–135].
responses may contribute to progressive immunodeficiency
[10,146].
4.2. Expression Pattern of IFNAR. Type I IFN are generally
consideredtoexerttheirbiologiceffectonvirtuallyallhuman
cells. This broad and noncell specific activity reflects the 4.3.1.Ligand-ReceptorMediatedApoptosis. TypeIIFNposi-
prominentinnateantiviralfunctionofIFN-I,whichneedsto tivelyregulatestheexpressionoftumornecrosisfactor(TNF)
reachanypotentialtargetofviralinfection. familymembers,capableofinducingapoptosisincellswhich
However, cell-specific differences in the responsiveness express specific receptors. Thus, expression of FAS ligand
to IFN-I signalling have been observed in humans, partic- (FasL),TNF-relatedapoptosisinducingligand(TRAIL)and
ularly among immune effector cells. Thus, IFN-I inducing programmeddeathligand(PDL)1,arealldirectlyregulated
TLR9 agonists, as well as HIV-1, efficiently upregulated the byIFN-Isignalling[21,146–148].
expression of the IFN-I regulated gene PDL1 on primary The contribution of the Fas/FasL system to CD4 T cell
humanmonocytesandasubsetofTlymphocytes,identified apoptosis during HIV-1 infection is well documented [149–
byselectiveexpressionofthechemokinereceptorCCR5[21]. 151], and similar findings were reported for IFN-I-induced
Analysis of IFNAR2 expression in T lymphocytes revealed TRAIL and its death receptor (DR)5 [55, 65, 121, 152, 153].
thatthissubunitofIFNARwasalmostexclusivelyrestricted TRAILexpressionfollowingHIV-1exposureorinfectionhas
to CCR5+ T cell subsets, independent of whether CD4 or beendescribedinTcells,monocytes,andpDC[24,55,153,
CD8 T cells were considered [21]. A similar restriction of 154],andTRAILexpressingpDChavebeenshowntodirectly
IFN-IsignallingtoCCR5+TcellswasobservedwhenHIV- induce apoptosis of CD4 T cells in HIV-1 infected patients
1-inducedupregulationoftheTcellactivationmarkersCD38 with high viraemia [153]. TRAIL mediated apoptosis in the
andCD69wasanalyzedinvitro[9,140]. settingofHIV-1stimulationinvitrowasoriginallyreported
Inbothhumansandnon-humanprimates,CCR5expres- to affect CD4 T cells, but not CD8 T cells [55, 65, 152].
sionisgenerallyhigherinmemoryandeffectorTcellsubsets Interestingly,TRAILmediatedCD4Tcellapoptosisdidnot
[141–144], and natural disease-resistant SIV host species, require productive infection, and TRAIL expressing pDC
such as sooty mangabeys, show reduced levels of CCR5+ were reported to be unable to lyse HIV-1 infected CD4 T
CD4 T cells compared to disease susceptible hosts such as cells [155] possibly favouring the depletion of uninfected
humans and Rhesus macaques [142, 143]. The role played CD4ThelpercellsinthefaceofCD4Tcellviralreservoirs
by CCR5 as coreceptor for HIV-1 and SIV Env proteins, preservation. However, Zhu et al. later described TRAIL
providing the critical mechanism for envelope-membrane dependent apoptosis in HIV-1 infected macrophages, as a
fusion and injection of the viral RNA into the cytoplasm, result of the downregulation of a decoy receptor [156].
providedthebasisforinvestigatinghowdifferencesinCCR5 Thus,TRIALinducedapoptosismaycontributetoregulating
Scientifica 7
the balance between clearance of HIV-1 infected cells and andTsg101isrequiredforthereleaseofvirionsfrominfected
depletionofCD4Thelpercells. cells,aprocesswhichisthereforeinhibitedbyISGylation[173,
Upregulation of PDL1 on circulating monocytes and T 174].
cellsduringHIV-1infectionwasoriginallydescribedtocor-
relate with active viral replication [157]. The report of a
4.4.2.MyxovirusResistance(Mx)GTPases. TypeIIFNind-
causativelinkbetweenIFN-IsecretionandPDL1expression
ucetheexpressionofproteinsinvolvedinmembranerearr-
afterexposuretoHIV-1alsoindicatedthatCCR5expression
angement leading to vesicle budding, organogenesis and
on T cells is associated with sensitivity to IFN-I signalling,
cytokinesis. Some of these proteins may contribute to host
determined by increased expression of IFNAR2 [21]. PDL1
resistancetopathogens,includingthep47andp65guanylate-
engagesitsreceptorPD1onTlymphocytestosuppressprolif-
binding proteins (GBP), inducible GTPases and the myx-
erationandinduceapoptosis[158].DuringHIV-1infection,
ovirus resistance (Mx) proteins [175]. In particular, the Mx
PD1 is highly expressed by exhausted dysfunctional HIV-1-
proteinshavebeenwidelystudiedfortheirantiviralactivity
specificTcells[159],andblockadeofPD1-PDL1interaction
andtheirexpressionisstrictlyregulatedbyIFN-I[176].
enhancesHIV-1-specificTcellimmunityandimmune-med-
TwoMxproteinshavebeenidentifiedinhumans,MxA
iated control of viraemia in humanized mice and simian
and MxB. MxA exerts inhibitory effect on a wide range of
models of HIV-1 infection [160–164]. Thus, upregulation of
viruses [167]. MxB was recently described as a novel restri-
PDL1viaIFN-Imaydirectlycontributetotheimpairmentof
ction factor for HIV-1 [177, 178]. The mechanism of HIV-
efficientantiviralTcellresponsesandtotheperpetuationof
1 inhibition is not fully elucidated, but the viral cycle is
HIV-1infection.
blockedafterviralentryandbeforeproviralDNAintegration
[177, 178]. In addition, binding to the capsid protein gag is
4.3.2.P53-MediatedApoptosis. Theexistenceofafunctional requiredfortheantiviralactivity[177,178].
connectionbetweenIFN-𝛼/𝛽andp53weformallyreported
by Takaoka and coworkers in 2003 [165]. The relevance 󸀠 󸀠
4.4.3. 2 -5 -Oligoadenylate Synthetase (OAS) and RNaseL
for IFN-I-induced p53 activation for viral infections was 󸀠 󸀠
Pathway. The 2 -5 -oligoadenylate synthetase (OAS) prote-
highlighted by Vilcˇek, who postulated that IFN-I-mediated
ins are IFN-I inducible enzymes which polymerize ATP
activation of the STAT1-STAT2-IRF-9 complex (ISGF-3)
into oligomers of adenosine generated with noncanonical
duringviralinfectionmaypromotep53geneexpressionvia 󸀠 󸀠 󸀠 󸀠
2 -5 bonds [179, 180]. These 2 -5 adenosine oligomers
twoISREsitesinthep53genepromoter[83].
induce activation of RNaseL, which mediates degradation
Doitshandcolleaguesreportedthattheaccumulationof
of RNA from invading viruses and suppression of cellular
reversetranscriptionintermediatesinCD4Tcellsundergo-
activities[181].DegradedRNAmayalsoactivatecytoplasmic
ingabortiveHIV-1infectionresultsinapoptoticdeath[166].
RLR,resultinginIFN-Iproductionandamplificationofthe
The apoptotic pathway induced by abortive infection was
antiviralinnateresponses[182].
associated with the production of inflammatory cytokines,
Specificanti-HIV-1activitybytheOAS-RNaseLaxishas
including IL-1𝛽 and IFN-𝛽, and involved activation of cas-
beendescribedintransfectedcelllines[183].Althoughthein
pase-1 and caspase-3 [166]. However, the authors found no
vivorelevanceofthisantiviralsystemforHIV-1inhibitionis
evidenceofp53involvement[166].
still to be determined, it is reasonable to speculate that the
nonvirusspecificeffectofRNaseLmaypartiallyaffectHIV-1
4.4.ViralRestrictionFactors. HIV-1infectionandreplication activityintargetcells.
withininfectedcellscanbeinhibitedatdifferentstepsofthe
virallifecyclebyrestrictionfactorsregulatedbyIFN-I.
4.4.4.ProteinKinaseRNA-Activated(PKR). Theproteinkin-
ase RNA-activated (PKR) is involved, together with other
4.4.1.InterferonStimulatedGene15(ISG15). The15kDapro- membersofthesamefamilyofproteinkinases,intherespo-
duct of the IFN-stimulated gene (ISG) 15 was originally nse to environmental stress. Kinases in this family regulate
identified as a ubiquitin homologue13. Similar to ubiquitin, therateofproteinsynthesisbyphosphorylatingthe𝛼-subunit
ISG15actsasatagforcellularproteinsviacovalentbinding oftheeukaryoticinitiationfactor(EIF)2,whichresultinthe
mediatedbyspecificenzymes,whicharealsopositivelyregu- sequestrationofguanine-nucleotideexchangefactorEIF2𝛽,
latedbyIFN-I[167–170].However,differentfromubiquitin, ultimately preventing the recycle of guanidin diphosphate
theprimaryeffectoftaggingwithISG15(oftenreferredtoas (GDP)whichisstrictlynecessaryforproteinsynthesis[184].
ISGylation)doesnotappeartobeproteasomaldegradation. PKR is constitutively expressed in all cell types in an
Forexample,ISGylationfavoursthesustainedproductionof inactive monomeric form and converts active homodimers
IFN-𝛽 in virus-infectedcells by preventingthedegradation followingautophosphorylationatkeyresidues[185–188].The
ofIRF3[171]andenhancesNF-𝜅Bsignallingbyinhibitingthe presence of two RNA-binding motifs in the N-terminal
activityoftheproteinphosphatase1B(PPM1B)[172]. regionallowsfordirectactivationofPKRbyRNA[189,190].
ISG15hasbeenshowntoexertbroadantiviralactivityin PKRisapotentinhibitorofHIV-1replicationinhuman
bothmiceandhumans[167].Theanti-HIV-1activityofISG15 cell lines in vitro, but exerts lower inhibitory activity in
ismediatedviainhibitionoftheubiquitylationofthecapside primarycells[191–196],questioningtheinvivorelevanceof
proteinGagandofthecellularproteinencodedbythetumor PKR-mediated anti-HIV-1 activity. HIV-1 messenger RNA
󸀠
susceptibilitygene(Tsg)101[173,174].UbiquitylationofGag containatargetsequenceatthe5 endwhichisrecognizedby
8 Scientifica
thetransactivatingaccessoryproteinTat;thetrans-activating TRIM22-mediated inhibition of HIV-1 replication [234].
response(TAR)RNAelementplaysacriticalroleinactivating Depending on the cell type and subcellular localization,
transcription [197–199]. PKR is sensitive to changes in the TRIM22caninhibitHIV-1transcriptionatnuclearlevel[234]
cytoplasmic concentration of TAR RNA sequences, in that orvirionproductioninthecytoplasm[204].
low amounts of TAR induce PKR activation, whereas high
TARRNAconcentrationsexertaninhibitoryeffectonPKR
4.4.6. Apolipoprotein B-Editing Catalytic Polypeptide 3
activity[200–202].
(APOBEC3) Proteins. The anti-HIV-1 activity of proteins
of the apolipoprotein B-editing catalytic polypeptide 3
4.4.5. Tripartite Motif (TRIM) Proteins. Members of the
(APOBEC3) family was originally described in an effort to
tripartitemotif(TRIM)proteinfamilyparticipateinabroad
characterize the function of the HIV-1 accessory protein
rangeofcellularfunctions,includingapoptosisandantiviral
virion infectivity factor (Vif), which is required for HIV-1
immunity[203].SeveralTRIMproteinshavebeendescribed +
replicationinprimaryCD4 Tcellsandcertaincelllines,but
fortheirabilitytorestrictretrovirusesreplicationandmany
not in fully permissive lines. Further studied demonstrated
aredirectlyregulatedbyIFN-Iinhumans,includingTRIM5
thatthehumangeneAPOBEC3Gisapotentinhibitorofthe
andTRIM22[204–208].
replicationofVif-deficientHIV-1[235].
TRIM5 is one of the best studied members of the
TheinhibitionofHIV-1replicationbyAPOBEC3G(A3G)
TRIMfamily,mainlybecauseofitsinhibitoryactivityagainst
relies on its cytidine deaminase activity on both RNA and
HIV-1. TRIM5 blocks HIV-1 infection in the cytoplasm,
DNA, causing the conversion of cytidine residues into uri-
beforereversetranscriptioniscompleted,byrecognizingand
dines[236–238].Thisprocessresultsinboththealterationof
binding the capsid protein lattice, thus interfering with the
thenucleotidesequenceandtheinsertionofnonnaturalbases
uncoating and ultimately with reverse transcription [209].
(uredines) into the DNA strand [236–238]. The enzymatic
The antiretroviral effect is strictly dependent on TRIM5 E3 󸀠
activity of A3G is selective for the third cytidine in 5-
ubiquitin ligase activity [210, 211], and is associated with 󸀠
CCCA-3 sequences[237,238].Asaconsequenceofcytidine-
proteasome recruitment [212, 213]. TRIM5 itself is ubiqui-
to-uridine mutation, the levels of HIV-1 cDNA in infected
tinated and degraded when it exert inhibitory activity on
cells are diminished. It was initially thought that uredine-
restriction-sensitiveviruses[210,211,214,215].However,itis
containingDNAwasdegradedbyhostDNArepairenzymes,
stillunclearwhetherubiquitinationofHIV-1capsidoccurs.
but inhibition of uracil DNA glycosidases is ineffective in
TRIM5 proteins from different nonhuman primate species
restoringHIV-1cDNAlevels[239].Ithasbeensuggestedthat
show varying potency of anti-HIV-1 activity. The macaque
A3Gactivitymayinterferewiththeprogressionofthereverse
andowlmonkeyTRIM5orthologueshavebeenparticularly
transcriptasealongtheviralRNAtemplate[240,241].
wellstudied,duetothepotentinhibitionofHIV-1infection
One important characteristic of A3G is the fact that,
in cells from these species [216, 217], which is associated
unless counteracted by Vif, it is packaged into assembling
withstronginteractionwiththeHIV-1virioncore[218].The
HIV-1virions[242].Thus,A3G-bearingvirionscantransfer
human TRIM5 orthologue shows relatively low inhibitory
therestrictionfactortotargetcells[237,243–245].
activity on lab-adapted HIV-1 stains [205, 219], but it is 10-
The viral accessory protein Vif potently inhibits the
foldmorepotentoncertainprimaryHIV-1isolates[220].
antiviral activity of A3G by recruiting it for polyubiquiti-
TRIM5 contributes to control viral transmission and
nation and proteasomal degradation, thus preventing A3G
replication in SIV-infected non human primates [221–225],
incorporationintonewlyformedvirions[244,246–248].
and differences in the rate of disease progression in HIV-
Other human APOBEC proteins have been shown to
1 infected patients correlate with TRIM5 expression and
exertanti-HIV-1activityinvitro.However,onlyAPOBEC3F
polymorphisms [226–229]. In addition, Battivelli and col-
(A3F) and APOBEC3H (A3H) haplotype II appear to have
leagues reported that HIV-1 variants selected by cytotoxic
a significant effect in vivo [249], even though they appear
T lymphocyte pressure to escape T cell recognition may be
to have lower potency and lower expression than A3G.
highlysensitivetorestrictionbyhumanTRIM5[230].
Accordingly,A3G,A3F,andA3HaretheonlyAPOBEC3pro-
In addition to its well-studied antiviral activity, TRIM5
teinscounteractedbyVif,suggestingadynamicevolutionary
has been the subject of studies characterizing its role as a
interplay between host restriction factors and viral escape
patternrecognitionreceptor(PRR)fortheproteinlatticeof
mechanisms.
retroviral capsid. TRIM5 is required for dendritic cell acti-
vation in response to lipopolysaccharide (LPS) [211], and
thesignaltransductionpathwaysinvolvingAP-1andNF-𝜅B 4.4.7.BoneMarrowStromalCellAntigen2(BST2,Tetherin).
are activated by TRIM5 [211, 231]. Thus, the interaction of Thebonemarrowstromalcellantigen2(BST2ortetherin)is
TRIM5withtheHIV-1capsidlatticeenhancestheinduction transmembraneproteinwithglycophosphatidylinositollipid
ofinflammatorycytokines[211]. anchor at the C-terminal domain, an extracellular 𝛼-helix
OtherTRIMproteinshavebeenstudiedfortheirability domain and a N-terminal transmembrane anchor [250].
to interfere with HIV-1 replication. Human TRIM22 effi- SimilartoA3G,tetherinwasdescribedastheIFN-I-induced
ciently inhibits HIV-1 transcription and replication in pri- cellular restriction factor inhibited by a HIV-1 accessory
mary human monocyte derived macrophages [232, 233]. protein,namelyVpu[85,86,251,252].Thus,intheabsence
TRIM22 exert its antiviral activity after HIV-1 integra- of Vpu, HIV-1 virions budding from productively infected
tion, and E3 ubiquitin ligase activity is not necessary for cells are trapped or tethered (hence the name tetherin) on
Scientifica 9
thesurfaceofinfectedcells[85,86,251,252].Tetheredvirions antiviralactivityofSAMHD1maybebiologicallyimportant
areeventuallyinternalizationandaccumulateinendosomes only in differentiated or non-dividing cells such as DC and
[251]. macrophages. The high rate of dNTP turnover in dividing
Tetherin exert antiviral activity on several families of cells,overcomingthedNTPaseactivity,mayinpartexplain
viruses[253–255],anditpreservesantiviralactivityintheface the susceptibility to lentiviral infection despite SAMHD1
of extensive mutations [256], suggesting that its function is expression. SAMHD1 can be upregulated in human mono-
notstrictlydependentonrecognitionofspecificviralprotein cytes and monocyte-derived DC by either type I or type II
sequences. IFN[279,280].
HIV-1 evades the antiviral effect of tetherin thanks to
theaccessoryproteinVpu[86,252].Vpudirectlybindsteth- 4.5. Immunostimulatory and Modulatory Activites. Type I
erin,andcausesageneraldecreaseintetherinexpressionon IFNplayapivotalroleinthetransitionfrominnatetoada-
thecellsurface[252].Differentmechanismshavebeensugg- ptive immune responses by both stimulating maturation of
estedtoaccountforVpu-mediatedcounteractingoftetherin APCandbydirectlymodulatingandshapingTcellfunction.
activity, including alterations of trafficking pathways [257,
258],andenhancedproteasomaldegradation[259–261]. 4.5.1.EffectofIFN-IonAPCDifferentiationandMaturation.
Other human and nonhuman primate lentiviruses have IFN-IstimulatesmonocytesdifferentiationintoDCinvitro
developed mechanisms of evasion for tetherin-mediated [281–284].However,thepresenceofIL-4intheinvitrocul-
antiviral activity. Thus, most SIV do not encode Vpu, and tureofmonocyteappearstomodifytheeffectsofIFN-I,likely
tetherin is antagonized by the Nef protein [262, 263]. Con- duetotheabilityofIL-4toattenuatetheexpressionofISG
versely,theEnvproteinofHIV-2,whichalsodoesnotencode [285]. Thus, the ultimate effect of IFN-I stimulation on the
Vpu,hasevolvedtointerferewithtetherinandcauseittobe differentiation of monocytes into DC may depend on the
sequesteredwithinintracellularcompartments[264,265]. cytokinemilieuinthesurroundingenvironmentandthetim-
ingofexposuretodifferentstimuli.
4.4.8. Sterile 𝛼 Motif (SAM) and Histidine-Aspartic (HD) Importantly, IFN-I promotes the maturation of DC to
Domain-Containing Protein 1 (SMAHD1). Studies on the fullycompetentAPCbyinducingupregulationofthecostim-
functionofanotherlentiviralaccessoryprotein,theviralpro- ulatorymoleculesCD40,CD80,andCD86andbyenhancing
teinx(Vpx),broughttothediscoveryoftherestrictionfactor theexpressionofMHCclassIandII[6,7,286,287].These
sterile𝛼motif(SAM)andhistidine-aspartic(HD)domain- changesinDCphenotypecorrespondtoincreasedabilityof
containingprotein1(SMAHD1). IFN-I-stimulatedDCtostimulateTcellproliferationinvitro
Vpx is expressed by HIV-2 and related viruses (such as [6,7,286,287].
SIVsm) but not by HIV-1 [266]. HIV-1 infection of human Following IFN-I stimulation, DC secrete IL-15, which
monocyte-deriveddendriticcellsisenhancedinpresenceof exertstimulatoryeffectsonTcellsandpromotesDCmatura-
exogenous Vpx or if HIV-1 is genetically modified to enco- tion[282,288].Inaddition,IL-10andtheTNFfamilymem-
de for Vpx [267, 268], and HIV-2 reverse transcription in bersBlymphocytestimulatorprotein(BlyS)andAPRILare
monocyte-derivedmacrophagesisstrictlydependentonVpx alsoexpressedbyDCfollowingIFN-Istimulation[289–291].
[269].AnumberofstudiescontributedtoidentifySAMHD1 WhenexpressedincombinationwithIL-10ortransforming
as the target of Vpx-driven ubiquitylation and subsequent growthfactor(TGF)𝛽,APRILcaninduceTcellindependent
proteosomal degradation. Thus, SAMHD1 ubiquitylation is immunoglobulinclassswitching[291].IL-10isapotentanti-
mediated by the cullin-4A ubiquitin ligase (CUL4A)-DNA inflammatory mediator, its production in response to IFN-
damage-bindingprotein1(DDB1)complex(CUL4A-DDB1), I highlights the dichotomous role that IFN-I may play in
which is assembled by Vpx via recruitment of the DDB1 balancingimmuneactivationandimmunesuppression[289].
CUL4Aassociatedfactor1(DCAF1)[270–273]. Accordingly,theeffectofIFN-𝛼/𝛽onIL-12productioncanbe
SAMHD1exertsphosphohydrolaseactivity,andcandeg- either stimulatory or inhibitory [292–294]. The maturation
radedeoxyribonucleotidestriphosphate(dNTP)todeoxynu- stageofDCandthedoseofIFN-Itowhichtheyareexposed
cleosideandinorganictriphosphate[274].Reversetranscrip- mayallaffectIL-12production,aswellastheinteractionof
tion relies on the availability of dNTP, and the anti-HIV- IFN-Iwithotherstimuli[295,296].Changesinthesecretion
1 effect of SAMHD1 is mediated via its dNTPase activity, of IL-12 may then affect the quality of the DC-activated T
which causes a reduction of the pool of intracellular dNTP cellresponsebymodulatingtheinductionofIFN-𝛾-secreting
toalevelincompatiblewithviralreplication[275].SAMHD1 cellsaswellastheproductionofothercytokines,suchasIL-4,
is exclusively localized in the nucleus [276–278], whereas IL-5,IL-10,andIL-13[289].
reverse transcription occurs in large part in the cytoplasm, ThesecretionofchemokineisalsomodulatedbyIFN-I.
suggestingthatdNTPhydrolysisinthenucleushasdeleteri- Monocyte-derivedimmatureDCsecretetheCXCR3-binding
ousrepercussionsonthecytoplasmicavailabilityofdNTP. chemokines CXCL9, CXCL11, and CXCL10 in response to
SAMHD1 is expressed at constitutively high levels by IFN-Istimulation[287].CXCR3isexpressedbyactivatedT
cells which are nonpermissive with regards to HIV-1 infec- andBcells[297],whichmayberecruitedtositesofinflam-
tion, such as monocytes and monocyte-derived DC [271]. mation. In addition, IFN-I induces DC-mediated secretion
However, HEK293T cells, undifferentiated THP-1 cells and of CXCL19 (MIP-3𝛽), which recruits naive T cells and may
+
activatedCD4 TcellsarenotrefractorytoHIV-1infection therefore contribute to initiating adaptive T cell responses
despite expressing SAMHD1 [270, 275], suggesting that the [298].
10 Scientifica
4.5.2.ModulationofTCellResponse. ThedirecteffectofIFN- (Section2.1).CombiningIFN-Iproductionwiththepotential
I on proapoptotic and immunoregulatory ligands, such as tomatureintoAPC,pDCmaybetheidealcandidatetopro-
FasL,TRAIL,andPDL1,hasbeendiscussedinSection4.3. moteefficientantiviralprimaryTcellresponses,byfavouring
The influence that IFN-I exert on APC maturation and CD4 T cell differentiation into Th1 cells and favouring the
cytokine production underscore the key role played in the activationandclonalexpansionofvirus-specificnaiveCD8
differentiationofbothCD4andCD8Tcells.Thus,theenha- T cells (Sections 3.1 and 4.5).The local production of IFN-I
ncementofIL-12productionobservedwhenDCarematured atthesiteofinfectionbypDCalsofavourstheinductionof
in presence of IFN-I, induces STAT4 activation and sub- antiviralmechanismswhichmaylimitthespreadofinfection
sequent T-bet expression in CD4 T cells, which drive the (Section4.4).
differentiation into IFN-𝛾-producing T helper (Th)1 cells When productive infection of some tissue target cells is
[299]. In addition, IFN-I directly act on human T cells to established, IFN-I productionmaybe sustainedby infected
induce STAT4 activation [300, 301], which is however not cellswhichdonotnormallyexertimmunefunction,butcan
sufficientonitsowntodriveTh1commitmentinvitro[302, react to viral genomes in the cytoplasm via specific sensors
303].Conversely,inpresenceofothercytokines,suchasIL-18 (Sections2.2and2.3).Althoughlimitedintermsofamount
andIL-21,IFN-IefficientlypromotesTh1celldifferentiation of IFN-I produced on a per cell basis, this second pDC-
andeffectorfunctions[304–306]. independentwaveofIFN-Iproductionmaybemorefocused
In parallel to the positive effects on Th1 differentiation, and circumscribed to the foci of potential viral replication,
IFN-ImayinhibitorreverseCD4Tcelldifferentiationinto and efficiently inhibit virus spread to other cells without
other Th types. Thus, Th2 responses are negatively regu- interferingwithadaptiveimmuneresponses.
lated by IFN-I in human cells via the suppression of the During HIV-1 infection, both the early pDC-mediated
Th2-drivingtranscriptionGATA-bindingprotein3(GATA3) and the late pDC-independent IFN-I responses may be
[304]. Furthermore, suppression of Th17 differentiation by dysfunctional and cause severe damage to the development
IFN-I has been described in both murine and human cells andmaintenanceofadaptiveanti-HIV-1responses.Thus,the
[307,308]. organizationoftheHIV-1envelopeintoafunctionallipidraft
IFN-ImayalsocontributetonegativelymodulateTcell may favour an overwhelming induction of pDC-mediated
response by regulating the function of CD4 regulatory T persistentIFN-Iresponsesoverantigen-presentingfunction
cells(Treg),whichplayacriticalroleinthemaintenanceof (Section3.1), which may prevent the efficient promotion of
immunological tolerance and homeostasis. Studies conduc- primary CD4 Th1 and CD8 T cell responses. Subsequently,
ted in patients with relapsing-remitting multiple sclerosis the tropism of HIV-1 for immune cells, including DC
have highlighted how administration of IFN-𝛽 treatment and monocyte/macrophages, may result in the prolonged
enhanced both the frequency and suppressive function of production of IFN-I in lymphoid tissues by HIV-1-infected
𝑇 cells[130]. professionalAPC,whichmaycompromisetheinductionof
Reg
The primary response of CD8 T cell against viral infec- secondary HIV-1-specific responses and contribute to the
tion, epitomized by proliferation and clonal expansion, can perpetuationofinfectionanddiseaseprogression.
be enhanced in presence of IFN-I, which is also critical in
allowing the generation of memory CD8 T cells [309–311].
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