Virus-Induced Disease: Altering Host Physiology One Interaction at a Time

ANRV319-PY45-10 ARI 16 June 2007 21:47

Virus-Induced Disease:Altering Host PhysiologyOne Interaction at a TimeJames N. Culver and Meenu S. PadmanabhanCenter for Biosystems Research, University of Maryland Biotechnology Institute,Department of Cell Biology and Molecular Genetics, University of Maryland, CollegePark, Maryland 20742; email: [email protected]

Annu. Rev. Phytopathol. 2007. 45:22143

First published online as a Review in Advance onApril 6, 2007

The Annual Review of Phytopathology is online atphyto.annualreviews.org

This articles doi:10.1146/annurev.phyto.45.062806.094422

Copyright c 2007 by Annual Reviews.All rights reserved

0066-4286/07/0908-0221$20.00

Key Words

virus-host interactions, symptoms, virus infection, host responses

AbstractVirus infections are the cause of numerous plant disease syndromesthat are generally characterized by the induction of disease symptomssuch as developmental abnormalities, chlorosis, and necrosis. Howviruses induce these disease symptoms represents a long-standingquestion in plant pathology. Recent studies indicate that symptomsare derived from specic interactions between virus and host compo-nents. Many of these interactions have been found to contribute tothe successful completion of the virus life-cycle, although the role ofother interactions in the infection process is not yet known. How-ever, all share the potential to disrupt host physiology. From thisinformation we are beginning to decipher the progression of eventsthat lead from specic virus-host interactions to the establishmentof disease symptoms. This review highlights our progress in un-derstanding the mechanisms through which virus-host interactionsaffect host physiology. The emerging picture is one of complexityinvolving the individual effects of multiple virus-host interactions.

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INTRODUCTION

In a susceptible host, plant viruses ofteninduce a number of common physiologicalalterations: decreases in photosynthesis, in-creases in respiration, the accumulation of ni-trogen compounds, and expanded oxidase ac-tivities (31, 42, 120, 136). Combined, theseand presumably other physiological effectsunderlie the display of virus-induced diseasesymptoms and provide the economic justica-tion for the study of these plant disease agents.Nevertheless, virus effects on host physiologyand symptom development are not well un-derstood. Undoubtedly, complexities in theinteractions between viruses and their hostshave greatly inhibited our ability to decipherthe pathways through which symptoms anddisease originate. Virus-induced symptoms inparticular have been difcult to understandin part owing to the intracellular replicationsite of these pathogens and the lack of spe-cic virus-derived metabolic products such asthe toxins and hormones that are associatedwith fungal and bacterial diseases. In addition,plant virus research has focused mainly on vi-ral genetics and the mechanisms of replicationand movement (85, 130, 136), leaving diseaseresponses relatively unexplored.

With the exception of host resistance,much of what we know regarding host re-sponses to viral infection is limited to theindexing of physiological changes within thehost (31, 120). More recently, studies describ-ing transcriptional and proteomic changes ininfected tissues have signicantly enhancedour descriptive understanding of host re-sponses (20, 27, 40, 41, 54, 129). How-ever, despite this increased understanding, themechanisms responsible for these physiologi-cal and molecular alterations remain largelyunknown, in part owing to the physiologi-cal variability associated with virus infections.Specically, virus effects may occur locallywithin the infection foci or systemically in re-gions distal from the site of infection. Virus ef-fects on the host also vary spatially and tempo-rally within the area of infection. These spatial

and temporal variations were clearly demon-strated by Wang & Maule (127) who identiedchanges in the levels of specic pea embryomRNAs in relation to an advancing virus in-fection front. Thus, like virus replication andmovement, effects on host physiology also oc-cur in a nonsynchronous fashion, making itdifcult to identify causal events in the devel-opment of disease among the ever-changingbackground of virus and host responses. Com-bined with environmental and experimentalvariations, these factors have made it par-ticularly difcult to link mechanistic causal-ities with the induction of specic diseasesymptoms.

Despite these difculties, recent studieshave begun to identify key interactions be-tween specic virus and host components thatcan be linked to the development of diseasesymptoms. The emerging picture reveals acomplexity of interactions functioning to pro-mote virus replication and spread within a hostwhile either directly or indirectly disruptinghost physiology. In this review we focus pri-marily on specic virus-host interactions thatform the basis of a causal chain leading frominfection to the display of disease symptoms.We also examine the mechanisms throughwhich virus components, protein or nucleicacid, redirect or disrupt host functions andhow these interactions lead to disease. Ourcurrent understanding is such that for certainvirus-host combinations it is possible to pro-pose testable models that address several long-standing questions in plant virology, such aswhy in the same host does one virus inducea severe disease symptom whereas a closelyrelated virus replicating at a similar level in-duces little or no disease, and how does thesame virus induce widely different symptomsin different hosts (31). Answers to these ques-tions will not only provide a more completeview of viral effects on host physiology butwill also promote a better understanding ofvirus replication and movement processes aswell as new insights into strategies designed toreduce the economic damage caused by virusdisease.

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The role of specic virus-host interactionsin replication, movement, or the suppressionof resistance clearly affects disease display,inasmuch as disease is an outcome of a suc-cessful virus infection. In this review, how-ever, the contributions of specic virus-hostinteractions in the infection process are notdirectly addressed. Similarly, virus-host inter-actions that contribute to localized host re-sponses or resistance such as the hypersensi-tive response are not covered. A number ofexcellent reviews covering these topics haverecently been published (14, 32, 60, 75, 103,110, 130).

MECHANISMS OF VIRUSPATHOGENESIS

Two general models have been used to explainvirus-induced symptom and disease develop-ment (37, 53). The competitive disease modelsuggests that plant viruses replicate within thehost to such an extent as to usurp a substan-tial amount of a plants metabolic resources,thus adversely affecting its growth and devel-opment. Alternatively, disease symptoms canarise through disruptions in host processesbrought on by the interaction of specic virusand host components.

Support for resource competition as acause in symptom development is found inthe degree to which many viruses comman-deer host transcriptional and translational ma-chinery. For instance, in Tobacco mosaic virus(TMV)-infected tobacco, viral proteins andgenomes make up 1% of the fresh weightof an infected leaf (80) whereas TMV trans-lation may account for more than half the to-tal protein production in infected cells (108).Similarly, declines in host gene expression,both at the transcriptional and translationallevels, have been observed at the site of virusreplication in infected plant tissues (81, 115,127). Presumably, the shutdown of host genesrepresents a method of increasing the avail-ability of host resources for virus synthesis. Inaddition, virus RNAs contain unique struc-tures, such as internal ribosome entry sites or

Competitivedisease model:viruses usurp asubstantial amountof host resources tocause disease

Interaction diseasemodel: specicinteractions betweenvirus and hostcomponents disrupthost physiology tocause disease

translation enhancer sequences, that providea competitive advantage over host mRNAs foraccess to the cells metabolic machinery (116).Thus, the ability of a virus to outcompete thecell for resources provides a simple explana-tion for virus-induced disease.

There are, however, many virus-host com-binations where variations in symptom sever-ity do not correlate with the level of virus ac-cumulation, suggesting that competition forhost resources is not a major contributor tothe disruption of host physiology. For exam-ple, symptom differences between two strainsof TMV were not attributable to resourcecompetition but rather to specic propertiesof the virus (6). Similarly, tolerance in peanutagainst Tomato spotted wilt virus (TSWV) isassociated with near-normal photosyntheticlevels in symptomless tissues even in the pres-ence of the virus (98). The transient natureof the infection cycle where virus replica-tion rapidly increases and then subsides, of-ten within a matter of hours, also suggeststhat virus sequestration of cellular resourcesis likely to be similarly transient, limitingthe competition for host resources. Further-more, reductions in host gene transcriptionand translation are often restored once virusreplication abates (81, 127). Thus, for manyvirus-host combinations competition for cel-lular resources may not be sufciently sus-tained to play a signicant factor in the ap-pearance of disease symptoms.

The interaction disease model of specicvirus and host components represents an al-ternative explanation to the competitive dis-ease model. Although more complicated thansimple resource competition, the induction ofdisease by specic virus-host interactions rep-resents a selective model that can explain thevariations in disease severity observed whencomparing similar viruses on the same hostor the same virus in different hosts. Evidencesupporting specic virus-host interactions asa determinant in the induction of disease issignicant. Outlined in this review are sev-eral studies that functionally demonstrate theinduction of disease symptoms via virus-host

www.annualreviews.org Virus-Host Interactions 223

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Consequentialvirus-hostinteractions:interactions thatdirectly contribute tothe establishment ofa systemic infection

Inconsequentialvirus-hostinteractions:interactions that donot contribute to asuccessful infectionbut can affect hostphysiology

RNA interference(RNAi): a cellularmechanism thatrecognizes andregulates/degradesRNA in a sequencespecic manner

interactions. These studies provide some ofthe rst mechanistic evidence as to howviruses trigger the cascade of events thatdisrupt host cell physiology and lead todisease.

Types of Virus-Host Interactions

Virus-host interactions can be grouped intotwo generalized categories (80). The rstcategory includes consequential virus-hostinteractions that directly contribute to theestablishment of a systemic infection; whilethe second covers inconsequential virus-hostinteractions, that do not contribute to thesuccess of the infection but neverthelessdisrupt host physiology. We now know ofnumerous virus-host interactions that con-tribute to the infection cycle (32, 75, 85, 103,130). These interactions, such as the bindingof the Tomato bushy stunt virus (TBSV) P19RNAi suppressor protein with siRNAs or theassociation of the potyviral VPg protein withthe cap-binding translation initiation factor,eIF4E, clearly demonstrate how viruses usurphost components to disarm host defensemechanisms and promote their own trans-lation and replication (67, 70, 71, 101, 109).Although we do not address the mechanismsthrough which these interactions functionto promote virus infection, many of theseinteractions also disrupt host physiologicalprocesses and potentially lead to disease.However, not all of these interactions appearto function in symptom display. Interactionssuch as the one involving the Tomato mosaicvirus replicase and host-encoded membranespanning proteins TOM1 and TOM3 are es-sential for virus replication but have not beenlinked to symptom display (133). In fact, si-lencing both TOM1 and TOM3 signicantlyreduced ToMV replication but did not affectplant growth (3). Thus, only a subset of thehost interactions may affect host physiology.

Interactions that are inconsequential tothe success of the infection process have notbeen particularly well studied, possibly be-cause without an effect on the virus life-cycle

they are more difcult to identify. However,such interactions may contribute to diseaseand tolerance phenotypes, explaining whycertain virus-host combinations result in asignicant disease response whereas a simi-lar combination produces little if any disease.Alternatively, these types of interactions mayconfer functions that are advantageous to thevirus only under certain environmental or tis-sue/cell conditions, making it difcult to iden-tify their importance in the virus life-cycle.What follows is a description of several virus-host interactions that have been linked to thedevelopment of disease symptoms. These in-teractions cover a wide range of virus andhost components, including protein and nu-cleic acid, and represent the complexity ofprocesses through which plant viruses inducesymptoms and cause disease.

HORMONE ANDDEVELOPMENTAL SIGNALING

Developmental abnormalities such as stunt-ing and leaf curling represent commonsymptoms associated with many virus dis-eases. It has been presumed that these typesof developmental symptoms are the result ofvirus-induced disruptions in plant hormonemetabolism. Numerous studies have demon-strated the effects of virus infections on theproduction and accumulation of various planthormones including cytokinins, auxin, andgibberellins (57). While these studies havefocused on monitoring hormone concen-trations and providing correlations with theappearance of symptoms, the underlyingmechanisms that induce these responses re-main elusive. Recently, interactions betweenspecic virus and host components havebeen linked to alterations in plant hormonesynthesis and signaling. Several of theseinteractions are discussed below.

Auxin Signaling

As a major plant hormone, auxin controls adiverse array of developmental and cellular


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responses (114). Recent studies on TMVinfection in Arabidopsis have identied aninteraction with the hosts auxin-responsivepathway that modulates the development ofdisease symptoms (90, 91). Specically, a yeasttwo-hybrid approach was used to identify in-teractions between the TMV replicase proteinand a subset of Aux/IAA proteins. Aux/IAAgenes encode short-lived nuclear proteins thatfunction as repressors of auxin-responsivetranscription factors (ARFs). The currentmodel for auxin signaling indicates that inthe absence of auxin, Aux/IAA proteins formheterodimers with ARF proteins, repressingtheir ability to modulate auxin responsegenes. In contrast, the presence of auxin pro-motes the ubiquitin-mediated degradationof Aux/IAA proteins through an interactionwith the auxin receptor F-box protein,TIR1 (30, 43, 63). Degradation of Aux/IAAproteins releases the ARFs to modulate theexpression of auxin-responsive genes involvedin auxin-mediated physiological responses(72). During TMV infection, the localizationof interacting Aux/IAA proteins was observedto change from the nucleus to the cytoplasm(Figure 1). However, a replicase mutant de-fective in its interaction with these Aux/IAAproteins did not signicantly affect Aux/IAAnuclear localization. This mutant producedattenuated disease symptoms even though itreplicated and moved at rates comparable tothe wild-type virus. Furthermore, silencingan interacting Aux/IAA protein resulted inthe display of a symptom-like phenotype,suggesting that these host proteins controldevelopmental processes that are similarto those disrupted during TMV infection.Combined, these ndings suggest that duringvirus infection interaction with the TMVreplicase protein promotes the relocalizationof a subset of Aux/IAA proteins, disruptingtheir normal function. TMV-mediated effectson Aux/IAA function occurred independentof the hosts auxin gradient, resulting in ARFactivation and changes in the transcriptionlevels of select auxin-responsive genes.Presumably, the inappropriate expression of

Figure 1Effect of TMV replicase protein on the localization of an interactingAUX/IAA protein (IAA26) fused to GFP. N denotes the nuclear location ofIAA26-GFP in uninfected tissues. In infected tissues, IAA26-GFP isrelocalized to cytoplasmic bodies that correspond with the viral replicaseprotein. Bars = 10 m.

ARF: auxin-responsive factor

TIR1: the F-boxprotein subunit ofthe ubiquitin ligasecomplex SCFTIR1

and the auxinreceptor promotingthe degradation ofAux/IAA proteins

these auxin-responsive genes leads to manyof the physiological and developmental ab-normalities that occur during infection. Thispossibility is supported by the fact that 30%of the Arabidopsis genes displaying tran-scriptional alterations in response to a TMVinfection contain multiple auxin-responsivepromoter elements (41, 90).

Whether or not this interaction affectsvirus replication or spread is yet to be de-termined, but in light of the knowledge thatauxin is a growth-promoting hormone, itmay be advantageous to the virus to reg-ulate this pathway as a means to producea more favorable cellular environment forreplication. Alternatively, this interaction maybe linked to host defense responses. Re-cently, Navarro et al. (84) determined thatplant perception of a agellin peptide de-rived from Pseudomonas syringae results in thenegative regulation of the auxin receptor F-box protein, TIR1, and the repression ofauxin signaling (84). This downregulation ofauxin signaling was shown to restrict bacterialgrowth, suggesting a role for this process inplant-induced defense. Conversely, enhanc-ing auxin signaling through the overexpres-sion of a TIR1 paralog increased host suscep-tibility. It will be interesting to determine ifTMVs effect on auxin signaling plays a rolein overcoming this new determinant in hostresistance.


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GA: gibberellin

Gibberellin Synthesis

Rice dwarf virus (RDV) is a member of thegenus phytoreovirus and causes signicantdisease problems in rice. As its name implies,RDV induces stunting and leaf darkening inits host, symptoms that are characteristic ofGA-decient rice mutants. Studies have im-plicated the P2 protein of RDV as the viralcomponent controlling dwarf symptoms (118,140). Within the RDV virion, P2 functions asan outer capsid protein and is necessary forRDV infection of its leafhopper vector (88,134). However, P2 is not essential for virusreplication in rice, although a mutant con-taining an early stop codon in the P2 ORFproduces reduced levels of virus (118). Zhuet al. (140) used two-hybrid and coimmuno-precipitation assays to identify an interactionbetween the RDV P2 protein and the riceent-kaurene oxidase. ent-Kaurene oxidases arekey components in the synthesis of GA inplants and have been linked to dwarng in rice(47, 55, 99). Rice plants infected with RDVshowed signicant reductions in GA1, a ma-jor active GA component in rice tissues. Fur-thermore, treatments of RDV-infected plantswith GA3 restored the non-dwarf phenotypewhereas similar treatments with auxin, in theform of indole acetic acid, failed to affectRDV-induced stunting. Thus, in this systemthere appears to be a direct correlation be-tween the level of GA synthesis in infectedplants, the interaction of RDV P2 with ent-kaurene oxidase, and the appearance of diseasesymptoms, including stunting.

Interference in the rice ent-kaurene ox-idase may also interfere in the biosynthe-sis of phytoalexins. Zhu et al. (140) havespeculated that interference in the accumu-lation of defense-related phytoalexins in ricecould serve to make the plant more compe-tent for RDV replication. The inability of aP2-decient RDV to replicate efciently inrice does support a role for this virus proteinin the infection process. However, the abilityof P2 to inuence phytoalexin production andthe subsequent effect of phytoalexins on RDV

accumulation were not determined. Thus, arole for P2-ent-kaurene oxidase interactionin overcoming phytoalexin-mediated defenseresponse is at present undocumented.

Ethylene

Ethylene mediates a diverse array of plant re-sponses ranging from senescence to defense(121). In addition, increases in the produc-tion of ethylene typically occur during virusinfection and are associated with the develop-ment of chlorotic and necrotic symptoms (57,86). Although there are no known interactionsbetween virus and ethylene signaling compo-nents, there are studies linking specic virusproteins to alterations in the ethylene signal-ing pathway. One such example involves theability of the Cauliower mosaic virus (CaMV)P6 protein to function as a key symptom de-terminant during virus infection (22, 141).Studies have demonstrated that P6, when ex-pressed alone as a transgene, is sufcient to in-duce a symptom-like phenotype that includesstunting, chlorosis, and vein banding (22). Alink between P6 expression and the disruptionof the ethylene response pathway is suggestedby the nding that P6 transgenic Arabidop-sis plants also display an ethylene-insensitivephenotype, with transgenic seedlings exhibit-ing a reduction in apical hook formationand hypocotyl shortening (40). Furthermore,genetic studies have indicated that a singleplant locus modulates the symptom-like phe-notype produced in P6 transgenic plants aswell as the ethylene-insensitive phenotype(40). The identity and function of this lo-cus is at present unknown. However, thesendings indicate a role for the P6 proteinin mediating changes to the ethylene path-way. Furthermore, CaMV infection in theethylene-insensitive plant mutants etr1-1 andein2-1 is signicantly reduced, suggesting el-ements of the ethylene pathway may affectvirus biology (74). Thus, ethylene appears toplay a role in regulating host susceptibility toCaMV.


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Developmental Signaling

RNAi has been the subject of numerous stud-ies describing its mechanism, role in viral de-fense, and effects on host and virus biology(11, 16, 123). In terms of host interactionsleading to disease, suppressors of RNAi havebeen shown to play a direct role in disruptinghost physiology and development, includingkey factors in hormone responses. Specically,the viral suppressors HC-Pro, p21, p19, andAC4 from Turnip mosaic virus (TuMV), Beetyellows virus, TBSV, and African cassava mo-saic virus, respectively, have been shown to al-ter the accumulation of micro-RNA regulatedhost mRNAs involved in several developmen-tal pathways, including the auxin-responsivetranscription factors ARF8, 10, and 17 (23, 24,61). These viral-derived RNAi suppressorsdisrupt the miRNA-guided cleavage of hostmRNAs leading to the accumulation of hostmRNAs that would normally be degraded.Alternatively, viral suppressors such as theTurnip yellow mosaic virus p69 protein, whichtargets a different step in the RNAi pathway,can lead to increased miRNA accumulationsand increased cleavage of target host mRNAs(25). At this time there does not yet appearto be any specicity behind the ability of vi-ral suppressors to disrupt miRNA function.Instead this disruption appears to be an indi-rect consequence of the viruss ability to evadeits hosts RNAi surveillance system. However,the severity of the symptoms caused by dis-ruption of RNAi pathways is determined byseveral factors, including the strength of thesuppressor function, the step in the silenc-ing pathway being targeted by the suppres-sor, and the ability of the virus and/or its sup-pressor to reach meristematic tissues wheremiRNA regulation is likely to have the great-est effect on host development (9, 58, 138).Thus, viruses such as TuMV with strong vi-ral suppressors that disrupt a common stepin miRNA pathway and are capable of infect-ing the apical meristem have the potential tointerfere with the accumulation of numerousmiRNA-regulated mRNAs, including those

Viral suppressor:viral-encodedmolecules thatmodulate host RNAidefense mechanisms

PD: plasmodesmata

MP: movementprotein

controlling radial patterning, hormone sig-naling, meristem identity, and owering (23,61). Under these conditions, it appears thata signicant portion of the disease symptomsproduced by these viruses result from the ac-tivity of the viral suppressor.

HOST TRANSPORT SYSTEMS

Virus movement through plasmodesmata(PD) and phloem occurs via several distinctmechanisms (73, 89, 103). However, all sharea requirement for virus-encoded movementproteins (MP) (117) capable of altering PDpermeability and size exclusion limits. As aconsequence, the transport of carbohydrates,small RNAs and proteins can be directly af-fected during virus infection, altering the al-location of cellular resources as well as cell-to-cell communication signals (12, 44, 73). Inaddition, the transport of mobile host com-ponents, such as proteins and nucleic acids,has recently been shown to be signicant inaffecting cell fate, development, and diseaseresistance (46, 52, 64, 77, 83, 105). Thus,virus interference in these transport processesrepresents a potentially effective means ofdisrupting host physiology. Despite this po-tential very little information exists regard-ing the identity of specic virus-host interac-tions involved in cellular/virus transport andtheir effects on host physiology. On the otherhand, specic physiological consequences ofthis virus exploitation phenomenon have beendocumented.

Carbohydrate Reallocation

Effects on carbohydrate allocation have longbeen associated with virus infections (5, 12).Studies have shown that active infection sitesfunction as photosynthetic sinks (49, 106,115), suggesting expanded availability of re-sources at the site of virus replication andmovement. The transgenic expression of MPsin TMV, Potato leaf roll virus (PLRV), andTomato spotted wilt virus (TSWV) has also


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Non-cell-autonomousproteins (NCAPs):molecules that movevia theplasmodesmata toaffect physiologicalfunctions in adjacentor distant cells

identied PD-related changes affecting themetabolism and allocation of carbon re-sources (4, 48, 51, 87). These studies haveshown that the expression of viral MPs leadsto accumulations of carbohydrates and starchin sink leaves. The effects of virus MPs on car-bohydrate allocation varies from virus to virus.For instance, alterations in carbohydrate allo-cation caused by the TMV MP do not corre-spond with MP-induced alterations in PD sizeexclusion limits nor with the induction of dis-ease symptoms (4). In contrast, the transgenicexpression of TSWV MP induces callose de-position at the PDs potentially blocking thesymplastic transport of sucrose and inducingdisease-like symptoms (96). Variations in theeffects of MPs on resource allocation likely re-ect the different mechanisms through whichthese virus proteins exploit the hosts trans-port system. Virus MPs have been shown toassociate with cell cytoskeletal and endoplas-mic reticulum (ER) networks (14, 75, 103), aswell as with a variety of specic host com-ponents including transcription factors, en-zymes, actin, tubulin, and chaperones (103).Thus, virus MPs clearly function through di-verse mechanisms to subvert their hosts trans-port system. In addition, MPs such as theTombusvirus P19 protein also function as sup-pressors of RNAi (125). From these ndingsit seems likely that virus reallocation of hostresources represents a general function of in-fection. However, the mechanisms throughwhich this reallocation occurs are virus spe-cic and likely the result of interactions be-tween specic virus and host components.

Whole Plant Communication

Mobile populations of macromolecules,including non-cell-autonomous proteins(NCAPs), mRNAs, and micro-RNAs, con-trol numerous plant developmental andphysiological processes (73). The trafckingof these molecules occurs via PD and phloemin a manner that is consistent with thecell-to-cell and long-distance movement ofmany viruses. Like virus MPs, many NCAPs

function to regulate the size exclusion limitof PD and bind and promote the movementof host RNAs. In fact, the immunologicalrelationship between certain NCAPs such asthe CmPP16 of Cucurbita maxima, an RNAbinding NCAP, and the MP of Red clovernecrotic mosaic virus, along with the abilityof the tobacco NCAPP1 deletion protein toblock the function of the TMV MP indicatesan evolutionary and mechanistic similaritybetween the function of viral MPs and that ofhost-derived NCAPs (132, 135). This line ofstudy has led to the suggestion that functionsof viral movement proteins may disrupt thenormal trafcking of host-encoded signalmolecules.

Whether MPs or other viral proteins com-pete for the RNA or protein targets of spe-cic host-encoded signaling molecules re-mains to be determined. However, effects onhost physiology, such as elevated sucrose ac-cumulation, have been observed in distal tis-sues of infected plants that contain no de-tectable virus (106). This is consistent withstudies that have demonstrated changes inhost mRNA accumulation in advance of thevirus infection front (81, 115). Furthermore,specic viral genes, in particular RNAi sup-pressors proteins such as the White clover mo-saic virus TGB1 MP, have been found to in-hibit the systemic transmission of silencingsignals as well as induce host developmen-tal abnormalities when expressed ectopically(36, 124). These ndings indicate that plantviruses can affect host physiological and devel-opmental processes even at a distance from thesite of infection. While interference in hostcell signaling by viral MPs and RNAi sup-pressors provides an attractive mechanism toexplain distal disruptions in host physiology,it is not yet clear as to the role this type ofinterference plays in the induction of diseasesymptoms.

CELL REPROGRAMMING

In contrast to animal viruses, which pre-dominantly rely on receptor-mediated


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endocytosis for cell entry, plant virusesdepend upon wounds and thus lack theability to selectively target the type of hostcell they enter. As a consequence, plantviruses may enter cells that for developmentalor physiological reasons are suboptimal forreplication and spread. However, there is nowincreasing evidence that plant viruses utilizespecic host interactions to reprogram suchsuboptimal host cells in order to enhancetheir replication and pathogenicity.

The best example of cell reprogramminginvolves the nuclear replication of single-stranded circular DNA genomes of viruses inthe family Geminiviridae. Since geminivirusreplication utilizes host-encoded DNA poly-merase, it is benecial for the virus to replicatein actively dividing cells where DNA replica-tion machinery is abundant (45, 97). How-ever, apart from the meristem and endoredu-plicating tissues, most cells within a plant arenot actively dividing and present a potentialbarrier to efcient geminivirus replication. Tocircumvent this obstacle, geminiviruses haveevolved the ability to alter the cell cycle oftheir hosts as a means to enhance the pres-ence of needed host replication machinery.Geminivirus Rep proteins, also named C1:C2in mastreviruses, C1 or L1 in curtoviruses,and AC1 or AL1 in begomoviruses (28), areencoded by all geminiviruses and have beenshown to interact with a family of plant pro-teins involved in the negative regulation ofthe cell cycle (65, 131). These interacting hostproteins, called plant retinoblastoma relatedprotein (pRBR) for the type of optic nervetumor in which they were rst identied, areconserved in eukaryotes and function to regu-late E2F transcription factors controlling theexpression of genes such as the proliferat-ing cell nuclear antigen that are active duringDNA replication/S phase. Presumably, the in-teraction between the virus Rep and pRBRsdirects infected cells to re-enter S phase lead-ing to the production of host DNA replicationmachinery and providing a more appropriateenvironment for virus replication. A Tomatogolden mosaic virus AL1 mutation disrupting

pRBR: plantretinoblastomarelated protein

pRBR binding has been shown to greatly al-ter symptom development (65). However, thismutation also restricts the virus to vasculartissues so it is not clear if symptom changesoccur from the inability of AL1 to interactwith pRBR or from the reduced spread ofthe virus.

dsRNA SURVEILLANCE

A key antiviral mechanism in animal cells in-volves the binding of double-stranded RNA(dsRNA) by protein kinase R (PKR). Essen-tially, dsRNA generated during virus repli-cation binds to PKR, leading to its dimer-ization and autophosphorylation. PKR thenphosphorylates the eukaryotic translation ini-tiation factor 2 (eIF-2), resulting in thesuppression of protein synthesis and induc-tion of cell death (68). Animal viruses haveevolved a range of counter-defense strate-gies against PKR that include inhibiting PKRdimerization by the hepatitis C virus NS5Aprotein (39) and the preemptive binding ofdsRNA substrates by Adenovirus VAI RNAs(62). The ability of a virus to disrupt this path-way is a key factor in pathogenicity. A plantortholog of the dsRNA-dependent PKR in-hibitor, P58IPK, has been identied by its in-teraction with the helicase proteins of TMVand Tobacco etch virus (TEV) (13). Functionalstudies conrmed the ability of the plantP58IPK to rescue mouse PKR-induced celldeath in yeast. Increased levels of eIF-2phosphorylation during infection indicate thepresence of an active PKR pathway in plantswith functional similarity to animal pathways.P58IPK-silenced or -knockout plants show amarked necrotic response when infected witheither TMV or TEV. This cell death responsewas blocked by the transient expression of anonphosphorylatable eIF-2, further indicat-ing a role for the PKR pathway in mediatingthis necrotic plant response.

Presumably, the ability of the TMV andTEV helicases to interact with P58IPK func-tions to inhibit PKR-like kinase activity,preventing cell death activation. PKR-like


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activity has been identied in tissues infectedwith TMV and Potato spindle tuber viroid(PSTVd) (29, 50), but a candidate PKR genehas yet to be conrmed. In mammalian sys-tems P58IPK also interacts with an ER resi-dent kinase that similarly functions througheIF-2 to attenuate cell translation (38). Inplants, chemically induced ER stress leads tothe transcriptional up-regulation of p58IPK

and decreased phosphorylation of eIF-2. Yetdespite decreases in eIF-2 phosphorylation,no corresponding change in bulk cell transla-tion has been observed (59). This nding mayindicate that only select mRNAs are transla-tionally affected by P58IPK or that in plantsthe P58IPK pathway affects only the regula-tion of cell death during times of ER stress.Both TMV and TEV replicate in close asso-ciation and induce rearrangements in cellularER (79, 102). Thus, the interaction betweenviral helicases and P58IPK in plants may func-tion to block ER-stressmediated cell death,allowing the virus the opportunity to replicateand spread. Adding another twist to this storyis the recent nding that P58IPK functions asa cellular suppressor of RNAi (S.P. Dinesh-Kumar, personal communication). This nd-ing represents a possible link between the hostRNA surveillance pathways PKR and RNAi,both of which affect virus pathogenicity.

HOST mRNA TARGETS

Sequence-specic RNA-degradation con-ferred by the hosts RNAi pathway is involvedin the control of numerous host processes (10,123). This RNA-degradation is directed bydsRNA or self-complementary hairpin RNAsthat are typically processed into small inter-fering RNAs (siRNAs), typically 2125 bpdouble-stranded molecules. During infectionvirus-generated dsRNA and hairpin RNA canserve to generate siRNAs, selectively target-ing viral RNA degradation. A minimal se-quence identity of 19 nt between an siRNAand its RNA target is required for degra-dation (113, 122). Similar small sequencesimilarities between viral RNAs and host

mRNAs have been reported to represent apotential means through which viral-derivedsiRNAs could disrupt select host mRNAs(128). Such similarities have been identiedbetween the RNA of PSTVd and numer-ous plant-derived sequences (128). Nearlyall of the identied plant sequences corre-sponded to the virulence-modulating regionof PSTVd, suggesting that PSTVds abilityto induce disease symptoms may reside withRNAi-targeted disruption of select host mR-NAs. Consistent with this possibility, Wanget al. (128) demonstrated that tomato plantsexpressing a noninfectious hairpin RNA de-rived from the PSTVd virulence region dis-played viroid-like symptoms. Similar ndingslinking short sequence similarities betweenTurnip crinkle virus and host mRNAs have alsobeen found to correspond with the reducedaccumulation of the corresponding mRNAs inArabidopsis (F. Zhang & A. E. Simon, unpub-lished results). Combined, these ndings sug-gest that targeted degradation of host mRNAsequences that have sequence similarities withvirus or viroid RNA sequences represents apotential mechanism for altering gene expres-sion and host physiology.

PROTEIN MODIFICATIONAND PROCESSING

Within a cell, protein activity is often mod-ulated through posttranslational modica-tions that include phosphorylation, acety-lation, myristoylation, ubiquitination, andglycosylation. Although the effect of virus in-fection on these host plant processes is notwell studied, some viruses clearly encode theability to utilize or disrupt specic proteinmodication processes, thus potentially af-fecting normal host protein processing.

Acetylation

A cooperative interaction between the gem-inivirus (genus Begomovirus) nuclear shuttleprotein (NSP) and MP is required to facili-tate the movement of the viral genome from


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its nuclear replication site through the cyto-plasm and into adjacent cells. This process isregulated by the activity of the viral coat pro-tein (CP), which binds and sequesters progenygenomes, preventing their further participa-tion in active replication (93, 100). The vi-ral NSP has been shown to interact with anArabidopsis acetyltransferase protein (AtNSI,nuclear shuttle interactor) (18, 82). In gen-eral, acetyltransferases are important regula-tors of DNA-associated processes includingchromatin remodeling, transcriptional regu-lation, protein stabilization, protein transport,and cell cycle regulation (66, 111). AlthoughAtNSI interacted with NSP, it was found toactively acetylate the viral CP. Furthermore,the interaction between NSP and AtNSI wasrequired for virus infection and movement,suggesting that NSP recruits NSI to acety-late genome-associated CP. These ndingsindicate that viral NSP recruits AtNSI awayfrom its cellular targets as a way to promotethe acetylation of CP. CP acetylation pre-sumably reduces the afnity of the CP forthe viral DNA allowing NSP to bind and ex-port the viral genome from the nucleus (19).NSP also prevented the oligomerization andacetyltransferase activity of AtNSI, suggest-ing an inhibitory role for the viral proteinin the functioning of AtNSI (19). Althoughthe cellular targets of AtNSI are unknown,it seems plausible that interference in theirnormal regulation could directly affect hostphysiology. Consistent with this possibility isthe nding that NSP mutants reduced in theirability to interact with AtNSI produce atten-uated disease symptoms (18).

Phosphorylation and Kinase Activity

Protein phosphorylation represents a key reg-ulatory mechanism involved in the control ofnumerous virus and host processes. Duringinfection, virus protein phosphorylation reg-ulates both replicase and MP activities (56,107, 126). In a few instances, the phospho-rylation of virus proteins has been linked tothe activity of specic host kinases. For ex-

ample, a PD-associated Arabidopsis kinasePAPK (plasmodesmal-associated protein ki-nase) has been shown to phosphorylate theTMV MP in a functionally relevant manner(69). However, it is not clear if the phospho-rylation of viral proteins has a direct inu-ence on host physiology. In contrast, an inter-action between the geminivirus NSP proteinand several receptor-like kinases termed NIK(NSP interacting kinase) have been identiedand linked to effects on host responses (35,78). Specically, interaction with NSP greatlyreduced NIK kinase activity in vitro whileArabidopsis knockout lines for these kinasesshowed enhanced susceptibility to infection.These ndings led Fontes et al. (35) to suggestthat NIK-encoded kinases mediated antiviralresponses and that NSPs ability to modulateNIK activity functions to disrupt this defenseresponse. Similarly, Florentino et al. (34) de-termined that the geminivirus NSP also inter-acts with a proline-rich extensin-like receptorkinase that functions to enhance virus infectiv-ity, possibly by up-regulating NSP function.These combined studies indicate that host ki-nases and phosphorylation play a direct rolein facilitating virus functions and pathogenic-ity. However, additional studies are neededto identify the role these interactions play inmodulating disease.

Degradation/Proteasome

Host proteolytic functions such as theubiquitin-mediated proteasome pathway aremajor contributors in the regulation of manyhost-encoded processes including cell devel-opment and pathogen defense (137). For an-imal viruses there are numerous examples ofthe targeted degradation of specic host fac-tors affecting virus pathogenicity (8). In plantsthe role of the proteasome pathway in viruspathogenicity is less well dened. However,several studies indicate that plant viruses alsoappropriate or alter proteasome functions.Pazhouhandeh et al. recently determined thatpoleroviruses, a genus within the family Lu-teoviridae, encode an F-box protein, P0, that


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functionally interacts with the plant homologof Skp-1, a component of the SCF family ofubiquitin E3 ligases (92). This is of interestsince P0 functions as the viral suppressor ofRNA silencing. In addition, the ability of P0to interact with the Skp-1 homologue corre-sponds with the viruss ability to suppress si-lencing as well as establish an infection. Thesendings provide evidence that the RNAi sup-pressor activity of P0 functions by directingthe ubiquitin-mediated proteolysis pathwayto target an essential host component or reg-ulator of the silencing system. The identityof the targeted host component is at presentunknown so the precise mechanism throughwhich P0 functions to suppress silencing re-mains to be determined.

Within the family Nanoviridae, Faba beannecrotic yellows virus (FBNYV) encodes a 20-kDa protein that also functions as an F-boxprotein and interacts with a Skp-1 homologfrom Medicago sativa as well as pRBR pro-teins (2). As described above, the Geminiviri-dae REP1 protein interacts with host pRBRproteins as a means to reprogram the cellcycle and provide a more hospitable envi-ronment for replication. The potential abil-ity of the FBNYV 20-kDa protein to bindpRBR and function as an F-box protein sug-gests that this virus targets the pRBR pro-tein to the proteasome as a means to disruptits control over the cell cycle. In a relatednding, the Rep proteins from geminivirusesin the genus Begomovirus have been shownto interact with SCE1, a SUMO-conjugatingenzyme (21). Sumoylation occurs posttrans-lationally and results in the covalent attach-ment of a ubiquitin-like polypeptide calledSUMO. SUMO-modied proteins, includingspecic viral proteins, display altered func-tions including SUMO-directed protein lo-calization and transcriptional activation (15).Still to be determined is whether these gem-iniviruses evolved to use sumoylation insteadof ubiquitination as a means to affect pRBRfunction.

Virus-encoded proteins are also targetedto the proteasome. For example, the TMV

30 K MP and the TYMV 69 K MP aretargeted by proteasome-mediated proteoly-sis (33, 94). This degradation process occurslate in infection and may simply represent thenormal turnover of these proteins in the cell.However, for TMV, inhibitors of the 26S pro-teasome affected the ubiquitination of the MPbut not that of the replicase or CPs, suggest-ing a degree of specicity in the recycling ofvirus proteins.

In another study, HC-Pro from Lettuce mo-saic virus was found to interact with and causethe aggregation of the 20S proteasome (7).In vitro studies indicate that HC-Pro inhibitsthe catalytic endonuclease activity of the 20Sproteasome, although it is unclear if this is dueto interference with the RNase catalytic siteof the proteasome or protection of the targetRNA through HC-Pro binding (76). How-ever, this nding opens the possibility that thepotyvirus HC-Pro protein can modulate theproteasome pathway. How such a modulationwould affect the many functions of HC-Proincluding its RNAi suppressor activity, pro-tease activity, and aphid transmission functionremains to be determined.

HOST PROTEINRELOCALIZATION

At the cellular level, the relocalization ofhost proteins via interactions with viral com-ponents represents an emerging mechanismthrough which viruses affect host physiol-ogy. As mentioned above, the ability of theTMV replicase to block the nuclear localiza-tion of specic Aux/IAA proteins correlateswith the transcriptional alterations of auxin-responsive genes and the display of diseasesymptoms (Figure 1). In another system, theCP of Turnip crinkle virus has been found tointeract in Arabidopsis with a member of theNAC family of putative transcription factors(95). The ability of the TCV CP to interactwith this putative transcription factor, termedTIP, correlates with its ability to induce hy-persensitive resistance conferred by the Ara-bidopsis resistance gene HRT. Localization


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studies demonstrated that coexpression of theTCV CP with TIP blocks TIPs localizationto the nucleus (95). TIP possibly functions asa guard protein mediating the hypersensi-tive response derived from the resistance geneHRT. Clearly, this interaction appears to af-fect induction of resistance; however, otherpathogen effectors/components that functionin a guard-like capacity to induce resistanceoften contribute to more severe disease symp-toms in a susceptible host (1). Thus, it will beinteresting to examine the role of the TCVCP-TIP interaction in a susceptible hostbackground.

A third virus-host interaction shown to af-fect protein relocalization involves an inter-action between the Tomato bushy stunt virus(TBSV) P19 protein and a set of nuclear ALYproteins from tobacco (119). During the in-fection process the TBSV P19 protein func-tions as an RNAi suppressor, a cell-to-cell MP,and in the induction of symptoms (104). Inmammalian systems, ALY proteins have beenshown to function as a nuclear shuttle pro-tein for the transport of RNA from the nu-cleus and in conjunction with other host pro-teins as transcriptional activators (112, 139).ALY function in plants has not been deter-mined. In Arabidopsis there are four ALY pro-teins all of which have been shown to inter-act via yeast two-hybrid assay with the TBSVP19 protein. The two strongest P19 interact-ing ALY proteins, AtALY2 and AtALY4, werealso shown to relocalize from the nucleus tothe cytoplasm in the presence of P19. Whatrole this relocalization plays in virus biologyor symptom display is unknown. However, re-cent studies have found that interacting ALYproteins that maintain their nuclear localiza-tion in the presence of P19 are in fact func-tioning to relocalize the TBSV P19 proteinfrom the cytoplasm to the nucleus (17). ALY-mediated relocalization of P19 to the nucleusalso correlated with impairment in the RNAisuppressor function of P19. It is not yet clearwhat effect the disruption of P19 suppressoractivity has on TBSV pathogenicity. How-ever, these studies indicate that relocalization

Guard protein:molecules thatassociate with bothpathogen effectorand host resistanceproteins to controlactivation ofresistancegene-mediateddefense responses

can be directed by either viral or host com-ponents and represents a reoccurring mecha-nism through which the virus and host mod-ulate the outcome of infection.

CONCLUSIONS AND FUTUREDIRECTIONS

From the diversity of documented virus in-teractions that affect host physiology, thedevelopment of disease symptoms clearlyrepresents a complex interplay between inter-actions involved in virus replication, move-ment, suppression of resistance, and cellularreprogramming (Table 1). In this review wefocused primarily on virus-host interactionsthat either directly affect host physiology orhave the potential to subvert specic cell path-ways or processes. Because of time and spacelimitations we have not covered virus-host in-teractions that coordinate replication, move-ment, or the induction of defense responses.Nor have we specically discussed virus-hostinteractions where an effect on host physiol-ogy is unknown. Although we have not cov-ered these types of interactions, it is logical toassume that many are involved in establish-ing an infection and thus must be consideredpotential contributors in the development ofdisease.

For the most part, key determinants mod-ulating virus effects on host physiology ap-pear to be derived from the interaction ofvirus and host components and not from gen-eral metabolic perturbations caused by theoverproduction of viral components and com-petition for host resources. That these in-teractions are the driving force behind thedisruption of host physiology is not unex-pected, considering the viruss limited geneticinformation and its obligate host dependencyfor completion of its life-cycle. However,from an evolutionary perspective it might beassumed that virus-host interactions resultingin minimal perturbations in host physiologywould be favored, in that there is no obvi-ous advantage for a pathogen to signicantlyimpair its host. Thus, host interactions that


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Table 1 Virus-host interactions affecting host physiology

Virus componenta Host component Effect on host physiology ReferencesTMV replicase Aux/IAA proteins Alterations in auxin response pathways,

developmental symptoms(90, 91)

TMV replicase P58IPK (inhibitor of dsRNA activatedPKR)

Regulation of cell death (13)

TuMV P1-HcPro, BYVp21, TBSV p19, ACMVAC4, TYMV p69

RNAi pathway components Misregulation of miRNA targetedmRNAs, developmental symptoms

(2325, 61)

RDV P2 ent-Kaurene oxidase Gibberellin synthesis, dwarng (140)Geminivirus Rep proteins Retinoblastoma protein (pRBR) Cell cycle reprogramming (65)PSTVd derived siRNA Host mRNA Misregulation of host mRNA, induction

of disease(128)

TBSV p19 ALY proteins (nuclear shuttle proteins) Unknown (17, 119)Geminivirus NSP (nuclearshuttle protein)

AtNSI (Acetyltransferase) Disruption of AtNSI acetylation activity (18, 19, 82)

Geminivirus NSP (nuclearshuttle protein)

NIK kinases Reduce NIK kinase activity, disruptdefense response?

(35)

FBNYV 20-kDa protein(F-box protein)

Skp-1 and pRBR Degradation of pRBR? Cell cyclereprogramming?

(2)

aTMV, Tobacco mosaic virus; TuMV, Turnip mosaic virus; TBSV, Tomato bushy stunt virus; BYV, Beet yellows virus; ACMV, African cassava mosaic virus;RDV, Rice dwarf virus; PSTVd, Potato spindle tuber viroid; FBNYV, Faba bean necrotic yellow virus; LMV, Lettuce mosaic virus.

induce disease would be lost or modiedto favor interactions that maintain host in-tegrity and physiological balance. Yet symp-tom development remains unchanged formany virus-host combinations even after gen-erations of infection cycles. This suggests thatfor many virus-host combinations the devel-opment of disease is a necessary outcome fora successful virus life-cycle. Certainly somedisease symptoms are the result of virus at-tempts to circumvent host resistance. Thisseems to be the case for the effect of virussuppressor functions on host RNAi surveil-lance systems. The ability to overcome RNAiapparently supersedes any detrimental effectson the host conferred by the functions of thesuppressor. In other systems, selective pres-sure may favor virus-host interactions that re-sult in disease as a means to reprogram thecell to create a host physiology favorable forreplication, spread and transmission. This ap-pears to be the case for host interactions withthe geminivirus Rep proteins. Thus, the dis-play of disease symptoms may depend upon

whether or not it is more advantageous to thevirus to maintain physiologically disruptiveinteractions.

A requirement to maintain physiologicallydisruptive interactions represents a little ex-plored means of devising new virus resis-tance strategies. Mechanisms that amelioratesuch interactions could lead to new forms oftolerance, with plants displaying fewer eco-nomically disruptive disease symptoms de-spite virus accumulation. Alternatively, a strat-egy intended to enhance the effects of specicvirus-host interactions could be used to hyper-disrupt cell physiology so severely as to inhibitvirus replication at a localized level. Manypathogen effector proteins of plant resistancegenes are in fact important for pathogenicityin susceptible plant lines (26). Thus, plantsalready employ tactics to target, as a de-fense strategy, those pathogen-host interac-tions that disrupt host physiology and increasepathogenicity.

To date, studies investigating virus effectson host biology have focused primarily on


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the interaction between individual virus andhost components. However, these interac-tions likely occur as complexes composed ofmultiple host and virus components. Futurestudies that identify the components of thesecomplexes and determine their effects on hostbiology are needed to better understand themechanisms through which viruses induce

disease. Additionally, a better understandingof the downstream effects on the hosts pro-teome and transcriptome directed by specicvirus-host interactions is also needed. Ulti-mately, it is the inappropriate activity, expres-sion, or accumulation of these downstreamhost components that result in the display ofdisease symptoms.

SUMMARY POINTS

1. Specic virus-host interactions appear to be responsible for a signicant proportion ofthe physiological effects leading to disease. However, not all interactions, even thosethat are essential for infection, have an effect on host physiology.

2. A number of virus-host interactions have now been identied and linked to the induc-tion of disease. These interactions provide the basis for a causal chain leading frominfection to the display of symptoms.

3. Virus-host interactions affecting host physiology target a broad array of host processesincluding hormone regulation, cell cycle control, host transport, protein modica-tions, and others.

4. The emerging picture reveals a complexity of interactions leading to disease, somefunctioning to disrupt host physiology as a way to promote virus replication and spreadwhereas others affect host functions indirectly.

FUTURE ISSUES

1. Identify downstream genes and processes that are altered in response to specic virus-host interactions and assess their contributions to the disease process.

2. Explore the function of multicomponent complexes composed of both virus and hostcomponents and address their inuence on virus infection and disease.

3. Alter specic disease inducing virus-host interactions to attenuate or enhance theireffects on host physiology as a means to promote new disease resistance strategies.

ACKNOWLEDGMENTS

We thank those colleagues who provided information in the form of unpublished results. Wealso thank members of our laboratory for helpful discussions and comments. Studies in our lab-oratory on virus-host interactions are supported by grants from the United States Departmentof Agriculture and the National Science Foundation.

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