the host immune system recognizes and eliminates invading pathogenic microorganisms such as viruses , bacteria , and fungi .  
recently , the mechanisms by which the innate immune system recognizes pathogen have been extensively studied .  
pattern recognition molecules / pathogen recognition receptors ( prrs ) are classified into three families : toll - like receptors ( tlrs ) , rig - i - like receptors ( rlrs ) , and nucleotide binding - oligomerization domain ( nod)-like receptors ( nlrs ) [ 1 , 2 ] .  
the rlr family contains retinoic acid - inducible gene i ( rig - i ) and melanoma differentiation associated gene 5 ( mda5 ) .  
the nlr receptor family contains nod1 , nod2 , nlrp3 , nlrpc5 , nlrp1 , naip , and ciita .  
in addition , dna - dependent activator of interferon regulatory factors ( dai ) has been identified as a dna sensor .  
various microbial components are recognized as their vague and common molecular shapes by prrs .  
early responses against virus infection are initiated on recognition of pathogen - associated molecular patterns ( pamps ) by pattern recognition molecules , triggering two responses .  
one is the production of interferons ( ifns ) resulting in an antiviral state as part of the innate immune response , and the second is maturation of dendritic cells ( dcs ) to establish acquired immunity .   in order to establish an infection within a host
, viruses must escape from and/or suppress the immune system by various strategies .   an important strategy used by viruses
tlr signaling proceeds via two pathways : the myeloid differentiation factor 88 ( myd88)-mediated pathway , and the toll - interleukin-1 receptor ( tir)-domain - containing adaptor inducing ifn- ( trif)-mediated pathway [ 1 , 2 ] .   the former causes activation of the transcription factor nf-b , which activates various genes contributing inflammatory reactions .  
the latter causes induction of ifns , whose stimulation leads cells to antiviral state .  
tlr3 signaling activates irf-3 , an important transcription factor for ifn- , and ifn production is induced .  
however , tlr4 activates both pathways , so tlr4 agonists activate nf-b and induce ifn production .  
cytosolic prrs , such as rig - i , mda5 , and dai , commonly activate irf-3 .   the expression of prrs differs depending on the cell type .  
importantly , it is different between cells derived from myeloid stem cells ( myeloid dendritic cells ( mdcs ) , monocytes , macrophages , langerhans cells , and neutrophils ) and cells derived from lymphatic stem cells ( plasmacytoid dendritic cells ( pdcs ) , t cells , and b cells ) .  
tlr7 and tlr9 are rarely expressed on mdcs , whereas tlr3 and tlr8 are rarely expressed on pdcs .  
tlr4 , on the other hand , is expressed at very low levels on both pdcs and mdcs .
initially , viruses invade the host epithelial tissues found in the oral cavity , respiratory tract , intestinal tract , and the urogenital apparatus ( figure 1 ) .  
lamina propria dcs , langerhans cells , and stromal cells are resident in these tissues .   in the connective tissues , fibroblasts resident , and capillary vessel and lymphatic vessel are expanded .  
monocytes , macrophages , t cells , b cells , pdc , and mdc circulate within the blood vessels and lymphatic vessels , and patrol the interstitial spaces .  
virus - infected epithelial cells and fibroblasts produce ifns , mainly ifn- and ifn- , which provide surrounding uninfected cells with antiviral state .  
furthermore , chemokines and cytokines , such as interleukin-1 ( il-1 ) , il-6 , il-8 , granulocyte - macrophage colony - stimulating factor ( gm - csf ) , and tumor necrosis factor- ( tnf- )   are also produced .  
these molecules promote chemotaxis of the resident dcs ( lamina propria dcs and langerhans cells ) toward virus - infected and dead cells .  
neutrophils , monocytes , macrophages , plasma cells , mdcs , and pdcs also migrate from the blood vessels to the site of infection .  
ifn--inducible protein 10 ( ip-10 ) , monocyte chemotactic protein 1 ( mcp-1 ) , macrophage inflammatory protein-2 ( mip-2 ) , mip-3 , and mip-3 largely contribute to the transmigration of blood dcs .  
however , these blood - borne immune cells can also be infected by viruses , which can then modulate the production of various cytokines and chemokines .   to establish an infection ,
viruses need to suppress a number of host immune responses , the antiviral activity induced by ifns , the chemotaxis of immune cells induced by chemokines / cytokines , the maturation and activation of dcs , activation of nk and nkt cells , transmigration of mature dcs to the lymph nodes , and the differentiation and activation of t cells and b cells in the lymph nodes , for example .  
when viruses infect immune cells , such as dcs , the infected cells frequently show suppression of maturation and differentiation , suppression of cytokine receptor and costimulatory molecule expression , secretion of molecules that mimic cytokines and cytokine receptors , and so on .  
these strategies are used by the virus to inhibit the acquired immune response .   in addition
htlv-1 , which is a retrovirus , infects cd4 t lymphocytes , cd8 t lymphocytes , dcs , b cells , macrophages , and astrocytes , and preferentially replicates in cd4 t lymphocytes .  
htlv-1 causes latent infection as a provirus , whose genome is integrated into the host dna , and does not replicate in cells in g0 phase .  
when the infected t lymphocytes are stimulated with antigen presentation from dcs , they proliferate triggering htlv-1 replication .   during the replication stage , a viral protein , tax , activates nf-b and promotes the growth of infected cells via upregulation of il-2 and il-2 receptors [ 6 , 7 ] .  
nf-b also activates the long terminal repeat ( ltr ) of htlv-1 genome , which further enhances viral replication .  
the replicated virus induces a host immune response , and cells infected with virus are eliminated by the induction of cytotoxic t cells specific for htlv-1 tax .   in patients with htlv-1-associated myelopathy / tropical spastic paraparesis ( ham / tsp )
this leads to the rapid elimination of infected cells through the induction of proinflammatory cytokines and cytotoxic t lymphocytes .  
so , in order to escape from acquired immune responses ,   htlv-1 needs minimum replication and latent infection .
some virus proteins are known as negative regulators of replication .   the htlv-1 basic leucine - zipper factor ( hbz ) protein suppresses tax - mediated transcription activation of the viral ltr .  
p30 also contributes to the expression of tlr2 , tlr4 , and tlr9 , and activation of irf4 . in monocytes ,
the tlr2 gene promoter is regulated by the transcription factors sp1 , sp3 , and pu.1 , and the tlr4 gene by isre and pu.1 .  
p30 downregulates the expression of both tlr2 and tlr4 , because it binds to pu.1 and prevents it from binding to dna .
this leads to the suppression of dc maturation , and of their subsequent migration to the lymph nodes .  
furthermore , p30 suppresses the enzymatic activity of glycogen synthetase kinase 3 ( gsk3 ) through promotion of the phosphorylation of nine serine residues .  
this leads to the induction of il-10 , which suppresses the function of macrophages , and also the maturation and activation of dcs .  
in fact , serum il-10 levels are elevated in patients with adult t lymphocyte leukemia .  
these immunosuppressive properties of il-10 indirectly contribute to the inhibition of virus replication and to the suppression of virus - induced immune responses .   
activation of infected t lymphocytes by dcs in the lymph nodes and cell - to - cell transmission of virus are considered to be important for virus proliferation in human .  
the viral p12 protein suppresses cell surface expression of both mhc class i and the il-2 receptor , and also suppresses linker for activation of t cells ( lat ) , which is an adaptor protein required for t cell activation .  
this results in suppression of t cells and dystunction of the stimulation / activation by dcs via the t cell receptor .  
htlv-1 causes proliferation of infected cells rather than virus and suppression of host immune responses , which helps it to maintain a latent infection in order to survive .
hiv can infect cd4 t lymphocytes , monocytes , macrophages , and dcs , and    preferentially replicates in activated t lymphocytes and activated macrophages .  
hiv establishes a latent infection in resting t lymphocyte , and t lymphocyte activation by dcs or stimulation with il-2 is thought to trigger active replication of the virus .  
apolipoprotein b mrna editing enzyme catalytic polypeptide - like 3 g ( apobec3 g ) is important for this resistance [ 16 , 17 ]
.   the antiviral mechanisms of apbec3 g are considered to act via inhibition of viral reverse transcriptase ( rt ) .  
it also produces a transition ( g to a ) in the dna strand transcribed by rt due to its cytidine deaminase activity .   however , a mutant lacking cytidine deaminase retains antiviral activity .
low molecular weight complexes of apobec3 g ( lmm : 70100  kda ) have antiviral activity , but   high molecular weight complexes ( hmm : 700  kda ) do not .   the vif protein of hiv converts lmm to hmm , and promotes proteasome - dependent degradation of the complex , so hiv can counteract its antiviral activity .  
t cell activation leads to conversion of lmm to hmm ( proviral environment ) .  
on the other hand , ifns induce lmm type ( antiviral environment ) [ 19 , 20 ] .      during the early stage of hiv infection ,
clinical symptoms show sings of immune system activation such as flu - like symptoms , rather than immunosuppression .  
immunological activation is caused by rna40 , an oligonucleotide derived from hiv , which activates pdcs , mdcs , t lymphocytes , and monocytes via tlr7 and tlr8   .  
the virus proteins , tat and vpr , induce proinflammatory cytokines via activation of nf-b [ 22 , 23 ] , which then enhances the transcription of the virus genome via the ltr .  
il-8 also contributes to the propagation of the virus via the accumulation of t lymphocytes .   
so , hiv maintains a latent infection in order to survive within the host .  
the vpu protein suppresses nf-b activation by inhibition of proteasome - dependent degradation of ib .  
this causes suppression of tnf- production by macrophages via tlr4 signaling .   because tnf- is necessary for maturation and translocation of dcs ( including langerhans cells ) to the lymph nodes , downregulation of tnf- leads to suppression of acquired immune responses , and so prevents inhibition of virus proliferation by activated t lymphoctes .  
these strategies contribute to the suppression of hiv proliferation in the lymph nodes , and also inhibit the propagation of infection .  
cosuppressive molecules , such as b7-h1 on dcs and pd1 on t lymphocytes , are upregulated in patients with hiv , and induce apoptosis through their interaction with dcs and t lymphocytes .  
although , virus particles and virus proteins are found in the blood of hcv patients .  
immune responses against hcv may be weak , but infected cells are attacked and eliminated .   in order to survive in the host , hcv maintains a chronic infection by suppressing the host immune responses .  
both hcv core and ns3 proteins activate nf-b and ap-1 via stimulation of tlr2 , which requires tlr1 and tlr6 as costimulators , in monocytes and kupffer cells .  
this activation leads to the production of il-10 and tnf- , both found in hcv patients at a high titer .  
il-10 suppresses the maturation of pdcs and the activation of t lymphocytes , and induces apoptosis in pdcs .  
the ns3-ns4a protein complex , which is a serine protease , degrades trif and ips-1/cardif / mavs / visa , which are essential for cellular signaling via tlr3 , tlr4 , and rig - i .  
this shutting off of trif- and ips-1-dependent signaling results in the suppression of ifn- and ifn- production , and in dysfunction of mdcs .   
this leads to the shutting off of tlr7 and tlr8 signaling , and to the suppression of maturation and differentiation of pdcs .   on the other hand
, nf5a suppresses traf2 dependent nf-b activation via interaction with nf5a and traf2 , but suppress neither mek1 activation nor ikk-dependent nf-b activation .  
infected dcs are thought to affect the production of tnf- , tnf- signal transduction , and chemotaxsis and maturation .  
dysfunction of dcs , suppression of t lymphocyte activation , and a decrease in dc number due to apoptosis allow hcv to establish a chronic infection .  
it has also been reported that hcv - specific cytotoxic t lymphocytes share upregulated expression of the coinhibitory molecule pd-1 , and that signaling from pd-1l ( pd-1 ligand ) on dcs results in suppression of hcv - specific cytotoxic t lymphocytes .
measles virus wild strains ( clinical isolates ) recognize cd150/slam ( signaling lymphocyte activation molecule ) as a receptor
slam is strongly expresseed on memory t cells and b cells , but is also expressed on monocytes , t cells , b cells , and matured dcs .  
infection of slam - negative mucosal epithelial cells with measles virus   wild strains is thought to be mediated by an as yet unknown 
the ha protein of wild virus strain , but not the laboratory strain , induces cytokines such as il-1 , il-1 , il-6 , il-8 , and il-12 via the tlr2 signaling pathway .   
these cytokines activate and recruit immune cells to the site of inflammation , where the activated immune cells are infected with measles virus via slam .  
interaction of the ha protein with slam suppresses tlr4-mediated il-12 production , but not il-6 and tnf- production .  
however , il-12 production mediated by other tlr signaling pathways ( i.e. , not via tlr4 ) is unaffected by the ha protein .  
these observations suggest that slam is a coupling factor for tlr4 , and that   the ha protein inhibits this function .  
the ha protein also interacts with a c - type lectin , dendritic cell - specific icam-3-grabbing nonintegrin ( dc - sign ) on dcs , and activates the serine / threonine protein kinase raf-1 via the ras signaling pathway .  
dc - sign - mediated raf-1 activation induces phosphorylation of nf-bp65 on ser-276 , and its subsequent acetylation .  
that virus proteins are synthesized de novo , the host cells , such as monocytes and dcs , infected with measles virus show suppressed il-12 production and tlr signaling , via tlr2 , tlr4 , tlr7 , and tlr9 .
pdcs infected with the measles virus showed suppressed ifn production and dysfunction of maturation [ 39 , 40 ] .   
both monocytic cell lines u937 and thp-1 and human peripheral blood mononuclear cells infected with measles virus show markedly suppressed tlr2- and tlr4-mediated proinflammatory cytokine induction via nf-b and ap-1 .   however , epithelial cells infected with measles virus show constitutive activation of nf-b and proinflammatory cytokine production , and these are further enhanced by treatment with tlr agonists such as lipopolysaccharide ( lps ) .  
monocytic cell lines infected with the mumps virus , which also belongs to the orthomyxoviridae family , show constitutive activation of nf-b and constitutively high levels of il-8 production . in monocytic cells infected with the measles virus ,
lps - induced ubiquitination ( probably k63-linked type ) of tnf receptor - associated factor 6 ( traf6 ) is suppressed and does not form active complexes of tak1 , tab2 , and traf6 .  
an ubiquitin - modifying enzyme a20 , which is a host nf-b negative regulator , is upregulated in measles virus - infected monocytic cells , but not in infected epithelial cells .  
the promoter region of the a20 gene shares two nf-b binding sites and a negative regulatory motif , elie , which is located upstream of , and adjacent to the two nf-b binding motifs .  
measles virus p protein ( phosphoprotein ) interacts with the elie motif , and activates transcription of a20 .
p protein is thought to release the suppressed a20 transcription machinery independently of activated nf-b .  
.   however , the measles virus v protein , which is formed by rna editing of the p genome and has an n terminal amino acid sequence identical to that of p protein , does activate nf-b .  
the balance of the expression levels and time courses of the p and v proteins may also contribute to the cell - type specific suppression of tlr signaling pathways .
the ns1 protein of type a influenza viruses suppresses innate immune system signaling activated by the pamps , via tlr3 , tlr4 , rig - i , and mda5 system .  
the mechanism of suppression is mainly via inhibition of irf-3 phosphorylation , leading to suppressed induction of ifn-/ , and ifn-1 , 2 , and 3 .  
in addition , inhibition of nf-b and ap-1 activation in influenza virus infected cells leads to suppressed proinflammatory cytokine production , for example , il-8 and tnf-.   influenza virus ns1 protein is known to be a multifunctional protein able to inhibit the type i ifn induction , the ifn - induced antiviral activity , the binding and sequestration of dsrna , the interference with the host mrna processing , the facilitation of preferential viral mrna translation , and the inhibition of dc activation [ 44 , 45 ] .
rsv f protein causes tlr4-mediated nf-b activation during the early infection stages of infection that is dependent upon virus replication .  
il-1 , il-6 , and il-8 are induced via nf-b activated by the stimulation of tlr4 .   during the late stages ,
the viral g protein is produced , and secreted , which then suppresses tlr4-mediated signal transduction .  
the cysteine - rich ( gcrr ) region of the g protein is also important for nf-b suppression .  
following the interaction of virus proteins with host cell surface proteins , the viral m2 - 1 protein inhibits the translocation of rela , a component of nf-b , to the cell nucleus .  
expression of the viral nonstructural proteins , ns1 and ns2 inhibit activation of irf3 induced by tlr3 , tlr4 , and rig - i signaling , and also suppress ifn production .  
however , ns1 and ns2 proteins have little effect on nf-b or ap-1 activation , so the production of proinflammatory cytokines may be effectively induced in the rsv - infected cells .
orthopox viruses , including the vaccinia virus , produce proteins that mimic cytokine receptors , such as those for ifn- , ifn- , ifn- , il-1 , il-18 , and tnf- , and disturb the cytokine signal transduction system .   other viral proteins also disturb the intracellular signal transduction systems .  
the viral a46r protein has a tir domain , and interacts with myd88 and trif , suppressing both il-1 and tlr signal transduction , but not tnf- signal transduction .  
the viral   a52r protein binds to irak2 , suppresses traf6-dependent ikk and nf-b activation , and then inhibits production of il-8 and rantes .  
however , a52r also binds to traf6 and promotes polyubiquitination of traf6 , tak1 activation , mapkk6 phosphorylation , and activation of the jnk - p38 map kinase pathway .  
the viral n1l protein interacts with the ikk complex ( ikk-ikk-ikk ) , tbk1 , and ikk , and then suppresses the activation of nf-b and irf-3 .  
vaccinia virus not only suppresses proinflammatory cytokines , but also induces production of an immunosuppressive cytokine il-10 , which shifts the th1 response and suppresses cellular immunity .  
human monocytes infected with vaccinia virus produce il-10 , and this il-10 is then further upregulated by stimulation with lps . during the early stages of infection ,
the cytokines produced enhance both sensitivity to lps and the production of tnf-.   tnf-  suppresses the formation and maturation of virus particles , and induces apoptosis of infected cells .
the induction of tnf- is considered to be a host defense response .   on the other hand ,
the receptor internalization and degradation ( rid ) complex , which consists two e3 products , e3(10.4  k)/rid and e3(14.5  k)/rid , suppresses cell surface expression of fas , tnf - related apoptosis - inducing ligand ( trail ) receptor 1 , trail receptor 2 , and tnf receptor 1 [ 54 , 55 ] .  
this results in the shutting down of the tnf--mediated signaling pathways in the infected cells .  
lps - induced mcp-1 and il-8 production are suppressed through the inhibition of nf-b and ap-1 activation .  
rid does not alter the expression levels of tlr4 , and so is thought to affect other components of the tlr signal transduction pathway .
hcmv modulates nf-b activity during the various stages of infection .   during the early stages ,
nf-b then contributes to the induction of proinflammatory cytokines , to the expression of virus immediate early genes , and to the replication of the viral genome .   the viral us28 protein , which is a hcmv - encoded chemokine receptor , constitutively activates both nf-b and phospholipase c signaling pathways .   the activated nf-b mediates the upregulation of the host serine / threonine protein kinase , receptor - interacting protein - like interacting caspase - like apoptosis regulatory protein kinase ( rick ) .  
rick , which has a caspase - recruitment ( card ) domain , functions downstream of the pattern recognition receptors ( which include the tlr , rlr , and nlr family members ) and mediates nf-b and map kinase activation .
rick suppresses the replication of hcmv in cooperation with active nf-b and ifn- .   not to be outdone
, the late gene products of hcmv also suppress nf-b activation [ 60 , 61 ] .  
il-6 , il-8 , and mcp are not induced in hcmv - infected cells and chemotaxsis , activation , and maturation are all suppressed .
ebv mainly infects b cells , although it can also infect t cells , nk cells , and epithelial cells .   both the attachment of ebv to receptor cd21 and the interaction of the virus glycoprotein gp350-gp250 with tlr2 activate nf-b
.   the virus gb and gh proteins are also candidates for tlr2 ligands .  
immortalization of b cells by ebv infection is due to the activation of nf-b by the latent membrane protein 1 ( lmp1 ) , and antigen stimulation - like signaling of the b cell receptor by lmp-2 .  
tlr2 signaling suppresses the transcription of the tlr9 gene via activation of nf-b containing p65 protein .  
so downregulation of tlr9 and upregulation of tlr7 and myd88 are observed in ebv - infected cells .  
cell proliferation is thought to be driven by tlr7 signaling activated by virus rna , because the tlr7 antagonist irs661 suppresses cell division .
small rna encoded by the ebv genome ( ebv - ebers ) activates tlr7 signaling , and induces il-10 production .  
however , activated irf-5 is negatively regulated by ebv - induced irf-4 and a splice variant of irf-5 ( v12irf-5 ) .  
this suggests that the tlr7 signaling system play a role in the cell division of ebv - infected cells , and in the establishment of persistent infection .  
lytic infection and production of virus particles are observed during the late stage of ebv infection .  
this leads to the downregulation of proinflammatory cytokines , the upregulation of tlr9 , and the suppression of tlr7 function through interaction of tlr7 and tlr9 .
viruses modulate both the innate and acquired immune systems using a number of clever strategies .  
the goal appears to be to survive within the host for a long time , rather than efficient replication .  
excessive replication would lead to detection and elimination by the host innate and acquired immune systems , thus bringing about the death of the virus .  
the virus needs to strike a balance between activation and suppression of host immune response .  
it is likely that each virus has developed various strategies to modulate the host immune response individually , and viruses that have succeeded in creating a good balance between host and parasite have survived .
modification of tlr signaling is a promising strategy for treatment of cancer , allergy , and infectious diseases [ 64 , 65 ] .   especially , the immunomodulators should not generate resistant virus to drugs compared to antiviral drugs targeting viral proteins .   as an existing example of virus infection , imiquimod , which is a tlr7 agonist ,
have been applied to an infectious disease caused by human papilloma virus , namely , condylomata acuminata .  
several issues must be considered for the clinical application of tlr signaling .    among the greatest is assessment of what are keys of host defense or virus survival in view of a series of viral infection process .  
for example , human herpes simplex virus 1 ( hsv-1 ) requires activated nf-b for its efficient replication .   on the other hand
, nf-b has a key role in inflammatory reactions via transcription activation of proinflammatory cytokines , cell adhesion molecules , and mhc .  
thus , activation of nf-b is a double - edged sword for hsv-1 .   in the host side ,
for example , intestinal epithelial cells express low levels of tlrs and high levels of negative regulators of tlr signaling , such as tollip [ 68 , 69 ] .  
also , in intestinal immunity , nf-b activation in a subset tlr signaling in dcs and macrophages is suppressed by a negative regulation ibns .
the dysregulation of tlr signaling in the lumen of intestinal epithelial causes limit chronic inflammatory activation induced by commensal bacteria .  
various tlr polymorphisms have been found , and some of them are shown to contribute to dysregulation of tlr signaling .  
the dysregulation has been suggested to be linked with a number of disease sensitivity and condition depending on individual differences [ 71 , 72 ] . in conclusion ,
the molecular mechanisms involved in modulation of host immune systems , including tlr signaling , give us important hints on how to overcome infectious diseases caused by viruses .
 in order to establish an infection , viruses need to either suppress or escape from host immune defense systems . 
 recent immunological research has focused on innate immunity as the first line of host defense , especially pattern recognition molecules such as toll - like receptors ( tlrs ) , rig - i - like receptors ( rlrs ) , and nod - like receptors ( nlrs ) . 
 various microbial components are recognized by their vague and common molecular shapes so - called , pathogen - associated molecular patterns ( pamps ) . 
 pamps induce inflammatory reactions mediated by the activation of the transcription factor , nf-b , and by interferons , which lead to an antiviral immune response . 
 viruses have the capacity to suppress or escape from this pattern recognition molecule - mediated antimicrobial response in various ways . in this paper 
 , we review the various strategies used by viruses to modulate the pattern recognition molecule - mediated innate immune response . 