when a viral infection threatens cells , one of the first measures they take is to induce apoptosis to restrict viral replication and spread . dying this way , host cells are likely to generate specific signals aiming at triggering the immune system with innate and/or adaptative responses allowing the eradication of the invader . on the other hand , viruses have evolved a huge arsenal of strategies meant to either counteract or deal with this destructive process to ensure their survival . apoptotic cell death is accompanied by characteristic morphological changes ( cellular rounding - up and volume reduction , chromatin condensation , nuclear fragmentation , plasma membrane blebbing  ) and at a molecular level by the activation of first initiator and then effector cysteinyl aspartate proteinases or caspases . activated caspases act through a catalytic cys that hydrolyzes peptide bonds within the substrate , with a stringent specificity for asp residue at p1 position ( the nature of residues at positions p2 , p3 and p4 depending on the caspase ) . caspase substrates include a large number and variety of cellular proteins that participate through their cleavage to the strong apoptosis - related morphological changes , as well as other physiological processes . interestingly , viral proteins are also likely to be cleaved by caspases but until 2004 , only four of them were reported as such and suggested as advantaging the associated viruses through their cleavage . since , their number has greatly increased and at least 16 viruses are now known to express proteins that undergo caspase cleavage . here , we aim at updating these cleavages and discussing their biological relevance . from apoptosis inhibition to the improvement or attenuation of viral amplification , caspase cleavage of vps highlights a potential new fascinating viral strategy to handle apoptosis induction . therefore , many viruses have developed strategies to inhibit this process through various mechanisms . among them , inhibiting caspase activity through the cleavage of viral proteins constitutes an effective way to achieve apoptosis suppression ( table 1 ) . baculoviruses are invertebrate viruses that encode several antiapoptotic products including iaps , p49 and p35 . when lacking p35 , the baculovirus prototype autographa californica multicapsid nucleopolyhedrovirus ( acmnpv ) induces apoptosis and fails to replicate , whereas p35 rescue inhibits cell death and restores viral replication . interestingly , p35 is proteolytically cleaved on infection and the dqmd cleavage site is required for p35-mediated apoptosis suppression . p35 directly inhibits many caspases , including insect sf - caspase 1 , human caspases 1 , 3 , 6 , 7 , 8 and 10 and mouse caspase 1 . indeed , p35 cleavage products remain irreversibly associated to the caspase through a covalent thioester bond between p35 d87 residue and the caspase catalytic cysteine . although being 50%-related to p35 , p49 yet exhibits a different caspase cleavage site ( tvtd ) that confers to p49 its antiapoptotic properties . caspase suppression by p49 also involves its cleavage by and stable association to the targeted caspases although acting as a dimer . besides effector caspases , p49 also affects initiator caspases that p35 fails to suppress , like insect sf - caspase x and human initiator caspase 9 . rather similarly , the product of the orf390 gene expressed by the crustacean - infecting white spot syndrome virus ( wssv ) was also shown to exert antiapoptotic properties . insect cells sf9 stably expressing orf390 gene strongly resist both viral- and actinomycin d - induced apoptosis . like p35 and p49 , orf390 ( also referred as wssv449 or aap-1 ) is suggested to act as an inhibitor substrate and is able to block several caspases , including human caspases 3 and 9 as well as insect sf - caspase 1 in vitro . orf390 ability to suppress caspase activity is associated with consensual caspase cleavage sites : devd that targets caspase 3 , and vetd and lehd that are both required for caspase 9 inhibition . although each site specifically targets one protease , the three of them are needed to reach maximal caspase inactivation . for baculoviruses and wssv , these different invertebrate - infecting viruses encode proteins exhibiting active caspase cleavage sites , just as cellular substrates do , but with the special ability to irreversibly freeze the protease activity . this leads to a very potent and broad caspase inhibition , which keeps the host cell machinery available and fit for viral amplification . unlike the expression of antiapoptotic products , the requirement of apoptosis for viruses to survive is a way more counterintuitive strategy that yet has been evolved by several viruses and involves caspase cleavage ( table 2 ) . parvovirus aleutian mink disease virus ( amdv ) can lead , at a single cell level , to either permissive infection , namely high levels of both viral dna replication and production of viruses , or persistent infection with low viral dna replication and almost no production of progeny virions . on permissive infection this requirement was associated with ns1 protein being cleaved through two caspase 3 sites leading to five ns1-related products . when one site is mutated within amdv molecular clones , the viral production is strongly reduced and even aborted when both sites are disrupted . interestingly , wild - type ( wt ) ns1 protein , which exerts replicative and transcriptional functions , is mostly nuclear , but when one of its cleavage sites is disrupted , the protein remains cytosolic resulting in a dramatic decrease in ns1-dependent viral protein ( vp ) expression . ns1-related c - terminal products , also nuclear , are suggested to be actively involved in the transport of wt ns1 . conversely , without caspase activation , amdv amplification would be limited and that might allow this lytic virus to establish persistent infection . human papillomavirus ( hpv ) is mostly known to infect epithelial cells of the genital tract and cause cervical cancers . on epithelial differentiation , hpv induces a dna damage response that leads to caspase 3-dependent apoptosis . interestingly , hpv e1 , a protein involved in viral dna replication , is a target for caspases 3 and 7 at a site that is conserved in all genital hpvs and preventing e1 cleavage reduces viral amplification . when compared with chemically induced apoptosis , hpv - induced apoptotic markers are limited . hpv pro- and antiapoptotic properties might achieve a caspase activity threshold that is sufficient for e1 cleavage and viral amplification , but not lethal for the host cell . besides e1 , hpv e6 protein is cleaved by caspases as well , but the functional consequences remain unknown . orf2 encodes the precursor of viral capsid proteins , vp90 , whose processing yields vp70 . besides , hastv activates caspases 3 , 4 , 6 , 7 , 8 and 9 . 
 in vitro , caspases 3 , 8 and 9 are able to target vp90 but only caspase 3 or 9 silencing reduces vp70 generation on infection . interestingly , both intracellular vp90 processing into vp70 and progeny virion release are lost in the presence of a pan caspase inhibitor . however , in opposition to what was first suggested , viral release needs caspase activation but does not need vp90 processing into vp70 to be achieved . but yielding fully infectious viruses does require shorter polypeptides to be created through vp70 further processing by trypsin . thus , first cleaving vp90 to generate vp70 likely represents a crucial intermediate event during hastv infection . sars - coronavirus ( sars - cov ) is a fairly new rna virus responsible for a severe acute respiratory disease . sars - cov leads to either permissive or persistent infection , with strong cytopathic effects and high viral titers or the opposite , respectively . interestingly , the nucleocapsid protein ( n ) , that has both structural and non - structural functions , is proteolytically processed in cells undergoing a lytic cycle or ectopically expressing the protein . using a pharmalogical approach , n protein was demonstrated to be targeted by caspases 3 and 6 . on permissive infection , n protein localizes in both cytosol and nucleus while remaining cytosolic in cells undergoing persistent infection . moreover , preventing n from translocating to the nucleus by mutating its nuclear localization signal abolishes its cleavage by caspases . thus , permissive infection is associated with n being translocated to the nucleus and possibly its ensuing caspase cleavage . nevertheless , the mechanisms underlying viral replication , n subcellular localization and n caspase processing are unknown so far . in sharp contrast with baculoviruses and wssv , several very different viruses evolved to hijack apoptosis with caspase cleavage being required to reach optimal viral amplification . based on the well - described case of amdv , we can hypothesize that the caspase - related products created through cleavages display novel properties required for the achievement of the viral life cycle . in some cases , apoptosis induction by the host cell leads to exactly what is expected , namely viral attenuation , but surprisingly with the help of viral protein cleavages . the possible viral advantage resulting from such an event is discussed ( table 3 ) . kaposi sarcoma - associated herpesvirus ( kshv ) establishes long - term infections leading to kaposi sarcomas and can go through either latent or lytic cycle . when kshv is reactivated , orf57 ( or mta or ks - sm ) is detected by western blot as a doublet , with the smaller product being abolished by a pan caspase inhibitor . in vitro , caspase 7 , which is activated on kshv reactivation , and to a lesser extent caspases 5 and 10 , are able to process orf57 at detd. interestingly , coexpression assays show that orf57 cleavage product ( i.e. orf57 lacking residues 133 ) is no longer able to promote viral lytic gene expression . accordingly , complementing a stable cell line containing an orf57-null kshv genome with ectopic wt or uncleavable orf57 promotes lytic gene expression , while orf57 lacking residues 133 does not . consistently , the number of cell - free virus particles dramatically increases when caspase 7 is inhibited . thus , orf57 cleavage would prevent proper expression of its downstream targets and subsequent full reactivation of kshv , suggesting that it allows kshv to maintain a persistent infection . as described above , amdv ns1 protein is cleaved by caspases , which allows full viral replication . interestingly , amdv capsid proteins vp1 and 2 are also processed by caspases on viral infection or ectopic expression . the cleavage generates a stable 26-kda product , vpx , and can be partly prevented by the pharmacological inhibition of caspases 6 , 8 , 9 and 10 , and completely by a pan caspase inhibitor . besides , vp protein expression in either transfected or amdv - infected cells mainly activates caspase 10 , followed by caspases 6 , 9 , 3 and 7 , with caspase 7 as the more efficient in vp cleavage in vitro . amdv - g strain grows more efficiently at 31.8  c than 37  c . the alteration of the caspase site within amdv - g increases both vp and genomic copies production at the non - optimal temperature of 37  c and shows no significant effects at 31.8  c , suggesting that vp caspase cleavage attenuates amdv - g life cycle . in vivo amdv - g infection might thus be regulated by active caspases because it only occurs at 37  c . interestingly , ns1 cleavage favors viral dna replication while vp processing would limit the packaging of progeny virions . as it is possible that both ns1 and vp cleavages do not inevitably occur simultaneously depending on the pattern of activated caspases , it would result in either effective or attenuated viral replication and allow the virus to spread or persist . h-1 parvovirus ( h-1pv ) displays oncotropic and oncolytic features meaning it preferentially replicates in and kills transformed cells , mainly in a non - apoptotic manner . however h-1pv is able to activate caspases in non - transformed cells , leading to the cleavage of ns1 , a non - structural protein ( ns ) notably involved in viral dna replication and gene expression by transactivating p38 promoter , which controls the synthesis of capsid proteins . when ectopically expressed , ns1-nterm acts as a dominant negative on ns1-driven p38 promoter transactivation , and dramatically decreases viral production . moreover , a molecular clone expressing an uncleavable version of ns1 tends to generate more virions . as cancer cells are often refractory to proper apoptotic induction , we propose that h-1pv oncotropism is due , at least in part , to the inability of cancer cells to cleave ns1 protein , thus allowing strong virus production . on the other hand , ns1 cleavage would act as a sensor of antiviral defenses and accordingly attenuate viral amplification , likely to favor persistent infection ( our unpublished results ) . crimean - congo hemorrhagic fever virus ( cchfv ) causes severe coagulation dysfunction in humans . cchfv nucleocapsid protein ( np ) is an important structural protein also involved in viral replication and , when ectopically expressed with an apoptotic factor such as bax protein , it generates two fragments through cleavage at a consensual devd motif . a caspase 3 inhibitor and cells lacking caspase 3 both allows a one log - increase in the production of virions , which suggests that caspase activation is involved in cchfv attenuation . thus , np caspase cleavage and/or np - related products may participate to this attenuation although the mechanisms remain to be investigated . interestingly , the caspase cleavage site is conserved within all the strains that were checked , suggesting that it is an important feature for cchfv regulation . caspase cleavages of viral proteins can result in the attenuation of the virus . rather than a weakness of the virus , this might be considered as a way for the virus to adapt to the cellular context : as a result of such viral attenuation , the host response is largely reduced while the virus keeps its ability to replicate to some extent . although the consequences of several caspase protein cleavages have been elucidated , they remain elusive so far for others ( table 4 ) . influenza viruses are structured into ribonucleoprotein segments consisting of viral rna and viral proteins , the major one being the np . unlike avian np , np proteins from human influenza a and b viruses are long known to be caspase targets . human influenza with uncleavable (  avian - like ' ) np is dramatically less lethal for mice , along with lower viral titers and faster clearance than its wt counterpart . this argues for the involvement of np caspase cleavage in the virulence of influenza virus . but making avian np cleavable ( i.e. making the protein  human - like ' by introducing the same caspase cleavage site ) does not enhance the viral virulence as could have been expected . thus , modulating influenza pathogenicity through np caspase cleavage would be a specificity of human strains that can not be extrapolated to avian ones . the viral ionic channel m2 protein is also cleaved by caspases , likely caspase 2 and/or 3 in both human and avian influenza viruses and was shown to be associated with avian influenza pathogenicity . altogether , these studies highlight that modulating influenza caspase sites attenuates the virus although through currently unknown mechanisms . hepatitis c virus ( hcv ) often leads to chronic infection evolving to cirrhosis and possibly hepatocellular carcinoma . hcv core protein induces activation of caspases 2 and 6 , and interacts with viral ns5a protein that is cleaved by the activated caspases . ns5a caspase cleavage was first suggested to allow the removal of a c - terminal cytoplasmic retention signal along with the translocation of the c - terminal deleted ns5a to the nucleus , reminding what was already described for amdv ns1 protein . however , a study more recently reported a cytosolic localization of these c - terminal truncated forms of ns5a and no obvious role of ns5a caspase cleavage in its trafficking . although its characterization is well admitted , the functional relevance of ns5a cleavage is still debated . tgev infection is able to induce caspases 3 , 6 , 7 , 8 and 9 activation and the cleavage of the structural np n , leading to a stable 41-kda fragment ( n ) . n protein is targeted in vitro by caspases 6 and 7 , and less efficiently by caspase 3 . in hrt18jap1 cells , the infection causes apoptosis but is not productive , suggesting that caspase activation ( and possibly n caspase cleavage ) prevents progeny virion generation . however , caspase inhibition in this context does not restore any viral production . owing to the lack of satisfactory tools , human hrt18jap1 cells were used as a study model but might not be appropriate to reveal n caspase cleavage relevance , notably for virus production . further digging will thus be needed to understand the biological significance of n processing by caspases on tgev infection . fcv capsid protein is synthesized as a precursor further cleaved by the viral protease . however , a 40-kda product ( p40 ) is also usually observed at late stages of fcv infection and can be abolished with a pan caspase or a caspase 3/7 inhibitor . accordingly , fcv - infected cells undergo apoptosis as well as caspases 2 , 3 and 7 activation . only caspase 2 and far less efficiently caspase 6 process fcv capsid protein in vitro at cleavage sites that have not been described yet . as suggested for instance for amdv , cleavage of the capsid protein might impair particle assembly and participate to viral persistence but this has not been investigated either . adenoviruses gather more than a 100 species with about 40 being able to infect humans . adenovirus early region 1a ( ade1a ) encodes two major proteins , 12s and 13s , that are involved in the control of early viral gene expression through their interactions with the host cell machinery . in vitro , caspases 3 and 7 are able to cleave both 12s and 13s proteins , although the cleavage efficiency depends on the viral serotype . furthermore , when apoptosis is chemically induced in ade1a - transformed cells , ade1a levels decrease but can be restored using a pan caspase inhibitor . thus , although ade1a caspase cleavage is likely to occur , its existence on infection as well as its biological relevance for adenoviruses remains elusive so far . interestingly , ade1a - binding abilities to transcription factors such as cbp and tbp are affected by the cleavage , suggesting that it might modulate the expression of early viral genes . molluscum contagiosum virus ( mcv ) is a poxvirus that , like variola , exclusively infects humans . mc159p , an mcv protein , exhibits antiapoptotic properties by protecting cells from fas - induced apoptosis through caspase 8 inhibition but is not targeted by caspases . on the other hand , mc160p is not associated with any antiapoptotic abilities but in vitro , is cleaved by caspases 3 and 8 . when expressed through vaccinia virus , mc160p is also specifically cleaved by caspases on fas - induced apoptosis while mc159p remains stable , as expected . mc159p and mc160p being thought to be produced simultaneously , a balance might take place between mc159p antiapoptotic response and mc160p caspase cleavage . however , the pathophysiological significance of this balance is difficult to address because mcv does not grow in tissue culture or experimental animals . herpex simplex virus 1 ( hsv-1 ) causes lifelong infections affecting between 50 and 90% of the global population . but some variants including d120 mutant induce apoptosis and under these conditions , infected cell protein no . 22 ( icp22 or mr37,500 protein ) leads to an additional product ( mr35,000 ) that can result in vitro from icp22 cleavage by caspase 3 . neither the identity of the caspase site nor the biological relevance of icp22 cleavage has been further investigated yet . there are clear evidences concerning the relevance of viral protein caspase cleavages in the physiology of viruses ( figure 1 ) . coherently , such a modification is used to directly fight apoptosis and acmnpv as well as wssv express proteins acting as strong and broad inhibitor caspase substrates . for other viruses , caspase cleavage probably allows the removal of specific regions that reveals or eliminates functional domains or signals . in some cases , this leads to full viral amplification ( amdv ns1 , hpv e1 ) , with the striking example of amdv ns1 protein that needs to be cleaved by caspases to translocate to the nucleus and eventually exert its functions . on the contrary , caspase cleavage can result in the attenuation of the virus by generating new viral products acting as dominant negatives of ns proteins ( h-1pv ns1 , kshv orf57 ) or unfit for virus packaging when structural proteins are concerned ( amdv vp and possibly fcv capsid protein ) . interestingly , such attenuation at a cellular level might hold importance regarding the possibility for viruses to establish permissive and/or persistent infection at a higher scale ( i.e. multicellular organisms ) . the functional consequences of some viral protein caspase cleavages still remain debated or elusive because of the difficulty of investigating hazardous entities ( influenza , hcv ) , the multitude of strains and genotypes ( influenza , hcv , adenovirus ) or the lack of appropriate tools such as cellular or animal models allowing to recapitulate the viral life cycle ( tgev , mcv ) . when caspase cleavages of viral proteins work in too mysterious ways , it is sometimes concluded that they constitute a mechanism of degradation resulting from the host fighting back the infection . however , the caspase - related products detected are mostly stable , suggesting they could be somehow involved in the viral life cycle as mentioned right above . besides , knowing how high the mutation rates of viruses can be , or that some viral oncoproteins ( like v - rel ) adapted to resist caspase cleavage through evolution unlike their cellular counterparts , keeping caspase cleavage sites seems very unlikely if viruses do not somehow profit from them . as caspase cleavage of viral proteins occurs in all sorts of proteins ( structural or non - structural ) and in all sorts of viruses ( dna as well as rna ) , this suggests that it constitutes a strong strategy to handle apoptosis . by managing to use the molecular effectors of apoptosis to protect themselves from eradication without any additional genetic information required , there are clear evidences concerning the relevance of viral protein caspase cleavages in the physiology of viruses ( figure 1 ) . coherently , such a modification is used to directly fight apoptosis and acmnpv as well as wssv express proteins acting as strong and broad inhibitor caspase substrates . for other viruses , caspase cleavage probably allows the removal of specific regions that reveals or eliminates functional domains or signals . in some cases , this leads to full viral amplification ( amdv ns1 , hpv e1 ) , with the striking example of amdv ns1 protein that needs to be cleaved by caspases to translocate to the nucleus and eventually exert its functions . on the contrary , caspase cleavage can result in the attenuation of the virus by generating new viral products acting as dominant negatives of ns proteins ( h-1pv ns1 , kshv orf57 ) or unfit for virus packaging when structural proteins are concerned ( amdv vp and possibly fcv capsid protein ) . interestingly , such attenuation at a cellular level might hold importance regarding the possibility for viruses to establish permissive and/or persistent infection at a higher scale ( i.e. multicellular organisms ) . the functional consequences of some viral protein caspase cleavages still remain debated or elusive because of the difficulty of investigating hazardous entities ( influenza , hcv ) , the multitude of strains and genotypes ( influenza , hcv , adenovirus ) or the lack of appropriate tools such as cellular or animal models allowing to recapitulate the viral life cycle ( tgev , mcv ) . when caspase cleavages of viral proteins work in too mysterious ways , it is sometimes concluded that they constitute a mechanism of degradation resulting from the host fighting back the infection . however , the caspase - related products detected are mostly stable , suggesting they could be somehow involved in the viral life cycle as mentioned right above . besides , knowing how high the mutation rates of viruses can be , or that some viral oncoproteins ( like v - rel ) adapted to resist caspase cleavage through evolution unlike their cellular counterparts , keeping caspase cleavage sites seems very unlikely if viruses do not somehow profit from them . as caspase cleavage of viral proteins occurs in all sorts of proteins ( structural or non - structural ) and in all sorts of viruses ( dna as well as rna ) , this suggests that it constitutes a strong strategy to handle apoptosis . by managing to use the molecular effectors of apoptosis to protect themselves from eradication without any additional genetic information required ,
viral infection constitutes an unwanted intrusion that needs to be eradicated by host cells . 
 on one hand , one of the first protective barriers set up to prevent viral replication , spread or persistence involves the induction of apoptotic cell death that aims to limit the availability of the cellular components for viral amplification . on the other hand , while they completely depend on the host molecular machinery , viruses also need to evade the cellular responses that are meant to destroy them . 
 the existence of numerous antiapoptotic products within the viral kingdom proves that apoptosis constitutes a major threat that should better be bypassed . among the different strategies developed to deal with apoptosis , 
 one is based on what viruses do best : backfiring the cell on itself . 
 several unrelated viruses have been described to take advantage of apoptosis induction by expressing proteins targeted by caspases , the key effectors of apoptotic cell death . 
 caspase cleavage of these proteins results in various consequences , from logical apoptosis inhibition to more surprising enhancement or attenuation of viral replication . 
 the present review aims at discussing the characterization and relevance of this post - translational modification that adds a new complexity in the already intricate host  apoptosis  virus triangle .