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I I I I I I I I I I I I Il s I I . I rnyoma' A bgical extension of this hypothesis is the infererxx ttat afterations in the smooth muscle cell go-o- nome by chemical mutagens or vinuses may be involved in the smooth muscle cell proiiferation chardcteristic of human atherosGerosis. This tt*sis, in part, provided the ratiortale for testing the viral hypothesis in an animal modd that would produce an arteriopathy approxama6ng the human disease, Supporting such an idea is the ex- perimental observaqon of facal smooth cell profrferabon induced in the aortic intima of chickens treated with a chemical mutagen initiatien-pronwbon sequence." To extend these observations to the level of the ge- nome, Penn et al" reported the presence oftransforming DNA in samples derived from plaques of human coro- nary art.ries. Ptaque-derived DNA but not DNA from nor• mal human arteries had the capacity to transform NIH 3T3 ceils in virro. The transformed cell line was capable of forming turnors in nude mice. The oripinal observations regarding the presence of a transfomvng gene element have been eo¢endcd into an animal model of earty arterial plaques induced by administration of the carcinogen 7,12, dimethylbenz(a)enthracene to cockerels.'s Further studies on vascular smooth muscle derived from human plaques show enhanced expression of the proto- oncogene c~rryc.7° The concept that increased expres• s'brt of this transforrning gene is a generalized phenorrt- enon in atheros lerefc lesions has been challenged re- cently by Yew et al," who were unable to detect transforming activity in DNA isolated from atherosclerotic plaques of human carotid arteries. Nevettheless other laboraiories have detected a similar transformed phenio- type in cells derived from atherosclerotic lesions.7° This recent study reported the correlation of trartsformat;on with the absence of a 140-kd protein norrnaly secreted by these cells. Cther studdes have identified a 140-1cd antitumorigenic glycoprotein that acts as an anti- angiogenesis factor,7"O The loss ot this protein cerre- hdes with a transformed phenotype. Taken together, these Bndings raise the possibility that the transforming gene activity may represent ttrie loss of a normal anti- oncogene or a gene controlling cellular prolifen',DOn. Pr.- ase identity of the transforming 9sne or genes remains unidentihed. AlthouQh no transforming gene of viral origin has been identified to induce human atherosclerosis, the resutts of recent studies suggest tiat vascular ulls have the po- terttial to be transformed by viral genes. Natchtigat and colleeguess'.s" have shown thstt vascular smooth musGe cells can be transformed aftyrtransfection with a plasmid containirtg the BgIII N fragment (MTF9II) of HSV-2 Immor- tnlization is probaby ttsa most important attribute of trans- formation, because these cells normaly have a fmite life span in vr7ro.l' The transformed cells did not retain ttie viral DNA sequences, consistent with othsr models of Viral Pathog.n.zii of Atheroaclerosis 12fl5 Np Dewnyr Igg2, voL 739, Iva 6 HSV-induced trartsforrrtation. lnterestingy transfomtaiion of rat embryo cells by SV40 can result in marked accu- mulation of CE, apparently because of an alteration in the regulation of bw-density lipoprotein recepters.°' Thus these studies provide circumstantiat evidence that virally induced transformation can predispose to some of the characteris8cfsatures of atherogenesis. More studies are necessary to prove that the vessel wall actualy contains transformed cells that are part of the foam cell population in atherosclerodc plaque re9ions. In Figure 7, 1 have sum- marized three hypotheacal cytologic aherations induced by herpesvirus infection. The 2tthorogenic potential of vi- ruses in acute infection, chronic infection. with ongoing immunologic activation, and transfomsation of vascular smooth muscle ceUs is depicted. The mechanism of transformation by herpesvirus DNA fragmerrts has not been elucidated. Proposals have been made to irnpficate many factors, inctuding DNA stem Ioop structures, ribonucleotide reductase activity, mutagenesis, gene ampl'tfication, increased or altered expression of cellular genes, activation of endogenous viruses, protein kinase activity, and the possible interac- tjon between latency of the virus and transformatiort" No conclus+ve proof exists for any of these mechanisms. Rec.enty shuttle vectors have been empbyed to study sequence anaysis of the mutations induced in cellular DNA by HSV•1 `f Interestingly the maximal increase in mutatiort frequency was rtoted at 4 hours after HSV-1 infection, imp(cating an immediat"arly gene or early viral protein. :,,uence analysis of the chromosomal tragments may lead to information about putative cellular targets for the virally induced mutagenesis. Mutagenesis may be the explanation for a'hit and nn' mechanism of virally induced transforrnation.°6 Because vascular smooth muscle cells can be transformed by H51i-2,82 herpesvinus-induced transforrnation may be a contribu- tory mechanism to periods of uncontrolled growth in the athetosclerotic vessel wal1. This is an attractive proposal and needs to be explored experimentally. Herpesvirus Entry into Vascular Cells After s®veral decades of investigation, the pathway of herpesviral entry into cells shlt remains undefined, partly because of the cemplexity of the virion. Herpes simp4ex virus is a large DNA virus whose nucleocapsid is sur• rounded by a lipid envelope. Seven herpesvirus- encoded flfympmtdrs; (termed 98, gC, gD, gE, gG. gH, and gi) have been identified on the errvelope e7 Four of these, g(B), fl(C), g(D), and g(H), appear to play a role in infectivity. Three gycoproteins, g(Bj, g(D), and g(H), are essential for irtfectivity and appear to be invotved in the process of viral penetratian." The prvctss pamway by

1206 Hajjar .VP oa0sis 1991, VOL 139, hh s I I I I 2L nfironio , Yrf0otion I "1lwponr w Inpry': Immun. RAsponsr FUaAn9 gtomN fk0t0tSn00ytOkln• rfltlm .. - ,.. .1 •:... W.oi^• 5m rrottf.ntlon Figure ?. Tbnie ryrolagKalf,rraiiosu cuiuc.ri t ' by bslxs emus tnj.asrns A bjpor4eeie ModU Qyar.pulatsd 51fC pcorrWration depiaing wal inJertion of dx rxtal uxrll urbic6 ean rnd:am dree cytopadiolqgtc.eWa.• aclitz ISt»O[L 4$!d7 flOi lead !o a(1fffd o[l- !ulrs mo.fabology. /ipid axumular~on, al- tatd a>mdllwl~r nrvors: ClurvdJsosceioswl p.bp~ of cbe vr"ulz- ae!!s asid ucu+r is- Jlans,iaeion, wiib g•ou,d.,jaero•.and evroknit ntsase, pnaihfY naulting on .enoorb rnrc%rle oefl prolifewsian; chronic lnfealon, robicb mutd pravide ibe inu+tunolo,qic afrnuif fUr an ungontg erFl-"UdEu+.rt bsJfammaea.,v rr gorw uxb n4bequ" oaUuGr bftv%u*:n of t6o tV3sc! v4ll ttod+ng ao drsrku4.cs! ayroodb ANLYIQ cmll fsollfsaSYOn; d' tt.1t13(OfRU2ion, llfNd7 kadr ro II~ prOAfI/adtM sbKE a6e eelU (nu dw6 capaciry to dorenm8dau Rroutb aaid at!l dierisio~ approFirfarely. Re- P.•isreed widi Pa"sin'ia'r• which herpesviruses enter vascular cells to initiate an in- fecton, however, has not been completely cttiaracterized. We have become interested in the pathway of herpesvi- rus entry into vascular cells because the virus can induce arterial injury or activaGai associatad with lipid accretion and aff7erosclerosis. as discussed in previous sections. WuDunn and Spear'a have shown that the in'It;al at- tachmertt of virions to the cdl surface occurs when the virus binds to heparan sutiate. The virion envelope gy- coproteins involved in this attachment may inGude g(B) and g(D) or g(C). Recent studies in our laboratory,® and !n collaboration wittl ethers,°D suggest ihat after this ir+itial irrceraction. HSV-1 may use a basic fibroblast growth fac- tor (FGF) neceptor to enter some bovine and human en- dothelial and srnoottll musoie cells. Herpesviral infectiv+ty was partially blocked (<7t]9G) when the high-a}finity FGF receptor was blocked using FGF peptjdes that bind to tfe high-affinity FGF receptor. Not all vascular cells, such as the rat arterial smooth rnuscle cells, appear to use an FGF receptor complex as a major portal of entry for HS/ (preliminary observations). Tha reascns for this are un• ciear. We speculate that receptor density or receptor conforttsaf;on on the cell surface in specific animal spe- aes may alter the mode of viral penevatim In bovine ceUs, for example, we did observe thai the virus ap- p.ared to recognize the receptor, because our viral prepar-ations contained basic FGF. We believe that the virus uses FGF from the cell or matrix to penetrate other host cells (Figure 88). Of interest is the observation by Baird et aL90 that HSV preparations are capable of induc- ing phosphorylation of a 90-kd subsfrate that represents a specific intracellular response to basic FGF through activation of its receptor.80 M altemative hypothesis is that viral gfycoprote+ns interact directly with the receptor, perhaps because it may share some stnlcturat homolo- gies with basic FGF (Fgure 8A). One of the enveiope glycoproteins, g(D), is required for viral entry into cells, as evidenced by the following: 1) Mortoclonal antibodies that react specifically with g(D) inhibit virion uptake.°7 2) Mutant viruses lacking g(D) can adsorb to the cell sur- face, but carxrot penetrate °2 3) W-inactivated virions corttaining g(D) are capable of blocidng entry of HSV-1, whereas a similar quantity of inactivated virions lacking g(D) cannot inhibit virus entry.°2 The epitopes invoMed in g(D) function have been mapped with the use of de!etfon mutants and compie- mentation assays a'A` Specific mutations in HSV-1, g(D) have been stbwrt to correlate with neuroinvasiveness•w' Because g(D) is essential for virus penetration.92 this property may be due to the abi!'ity of the virus to penetrate cells of the peripheral nervous system and other organ syst.rns. Whether mutations in either the virion, cellular I I p9 t P'K ioa A4 Mse r6e~ via. dw t reo infe Cort OM use, cat cW er& atec I I I I I Gra , poR'

a I I I I I I I I I I I Viral Pathoflenstis of Atherosclerosis 1207 ~y/P pemnb.r Z491, VoL 139, Mn 6 } r F1pvn e. aorrbtr "xcbmrrtv oftYSVpvaevmro.t i,uo cssvlm arrts bv d~e basicJi7*v61aa grvuxh/aa~ (FCF) rtupra.. ru:o rncdecr miv prtyn+ad by uti~ ixrra sivrq~lae cvsa rHSSrI type 1, rnay piaim+ar~ t~cr.l~ aflx A: lnrac HSV Lisidr dbealy w die 6a+i'r fUFrrrepeo. owrrV ea t~+s p.~te.r eJ~ a~ n+~ slycoFsoret>as rpp) sue6 ar~prs~ ~CC„~ gFCVI. m~de.~rHJ o~e' od~Peio^ ro rbe avfoer of ea![r ay b.p~+ n~!/ait prxEOalyrvLt rHS Pe). SfofCCUlo~ mfmloy beru.+nvc t{ufe tou( g6CnpronYm am~dpasrions aJr6r fC'rF recepCVS>rap er.t4, 7bea I~PG nurv alfl ~u¢ ro nabil=e ~e HSV co~rP/ez on 86r isofcu of mr crilt by busncrlr,*g lcrurclly wkb tB.gA~vxbu: ffie v;ur tbo~ peneAa.s ~G. carn rt.ot.86 dmr t~sF .roepro.,, 8: r,raoQ NSV 'p~v4aGz" on fGF, dx +ma..al tf~d Jo. ~ FeP rn.pa; ajtrr ad"prion w dbe aN/ uia Hs•PG. FGF bis&dr to ia rrMor dbwly m+d ir 6uanaltwd buo dx c.K drP&ttng HSYaJon,q u+* a buo ebe eetC In bodr rnurins, orrr dae trts penevaaa Abe Gr!!, l+t tixn degrar ia sCpli=oss protrs Rep.inud uar6 pemissiortse receptors, or their expression will atter the susceptibilityr to infedion of individuals and their arteries are interesurx3 concepts, but they remain to be explored. Frortt a devei- opmerttal aspect, the concept that herpesviruses may use, in part, a growth factor or its receptor to penetrate cells in vivo is very intriguing bocaus® FGF levels in the celf have been liniced to processes related to cell differ- enbation, cell division, and aging that are often associ- ated witfl human atfteresclerosis. Summary Circumsrsntial evidence condrues to accumulate to sup- port the hypottasis that certain herpesviruses can cor~ tribute to specific paiho9enic events associated with ath- erosclerosis. This fncludes 1) evidence of widespread infection of herpes viruses in the fleneral population, wherein these viruses are found in the arterial wall, indud- ing lesiorrbcaring areas; 2) the recogni6on of the esso- aaiion between accelerated attwrosclerosis and CMV Infection in cardiac albgraft recipierus; 3) the demonstra- t;on of herpesvirus-+nduced art~.rosderosis occurring in animal models of the disease during normocholester- olemia; 4) profound mftects on chol8steror metabolism in human, bovine, and avian arterial smootr, muscle cdts infected with herpesvirusss, predisposing to free and es- teriTied cholesterol accumulation; 5) atterations in extra- cellular mztriz and enhancement of a procoaflulant milieu on vascular c.lls infected with herpesvirus in vitro; 6) in- duction of mortiocyte and PMN adhesion receptors on HSV-infected endotheliai cells; 7) transforming potentiat of herpesvuuses and the ability of vascular smaoih mus- cle cells to be transformed by such viruses: and finaliy, 8) the abiliry of herpesvirus to induce actnrati.on of specific cytokine genes that have been implicated in the growth regulation of the vessel wall during human atheragene- sis. Although the rea atior>ship of herpesvinuses and ait} erasclerosis wn humans is not unequivocalty direct, data are accumulzting triat indicate that specific viral vectors may ind@ed have a participatory role in the inducfion of arterial injury. This also includes activaDon of the coagu- la6on cascade with links to thrombotic processes and development of a complex aReriopattry, With the advent of the applicanon of new moiecuiar techniques to study transforming eu.ms in the arterial waN, undoubtedly new irtfortnation wili emerge regarding tte viral origin of atil- erosderosis. Acknowledgments The au>tar ttWks his fabws antl atwr cofleagues who particl- pamd in marry of the expernnents and Ciscussiorts about the irtterpretaDOns of thho worfc OaecriFed heroi+, TroesE indivibuals I

1208 Haj)ar NP De+-smbW 2991. YoC L39, Na 6 inchxie C. R'ctlerd Miniek. Cztherine Fabricant, Julius Fabricant. Domerlicic Falcdle, OrU Edngin. Ketlneth Porrerint2. Andrew Nichdsotl, RobeR Kaner, Timottly McCaNrey, and Roy S+7+~er- steirt Also the 8W1or wishes to Qratefully, acktlo+Aed9s Andrew Baird, Ctaud'a Basifico, Dario ARieti, Thcrtlas Edgingtan. Allm Man.xukfsani, Robert Fbrfdewic¢, end Hanroy Friedman for their coileborative effors. Fnaly many thanks ara earKled to Smn Smith, Aaron Marzus. Ralph Nachman, Michaef Gimbrale and RusseH Ross for the3r support and collegial advice everthe past 17 years. References 1. Schwars SM. Carnpbe0 GR. CampW JH: Repficadon of srrqctl~ muscle cdis in vaacular dlsaase. Cirt: Res 1886. 68:427-A4d 2. Rass R: Athernscbrosis; A probLem of the biofogy of arterial walt caUs and tfleir irlterIIcfiOns with bbod arnporlents. Ar- tetoscletnsis 1981, 1:293-,311 3. Ponwrantz KS. HaDar 0P: Etcasarbids in the regulation of arterial srnooth rruSSJe coll phenotype, prdiferative capac- iiy, and choie:,lrol metabcaism. Artenascterosis 19M, 9A 13- • d29 4. Benditi EP, Benditt JM: Eridence for a monocbnal origin of human asherosderodc plaques. Prno Nat Acad Sd U S A 1973, 70:1753-1756 5, Fabri= CG, Krook L, GiUecpie JH: Virus-induced chdes- terol crysrals. Science 1973, 181:566-567 fi Fabr'scant CG, Fabricant J, Lltrenta MM, Mhdc CR Virus- irtduced atneroeclLrosis. J Exp Med 1978. 148:33S.W 7, Minick CR, Fabricant CG, Fabricant J, Lttrenta MM: Aftroarterioscierosis induced by nkCtien v,if1 a nerpesti~- ruz. Am J Pafhd 1979, 96:673-fi6 8. Fabticarft CG. Fabrican[ J, Meicfc Cf3, Urenta MM: Herpes- virus indueed ameroscierasis in chitdcers. Fed Proc 1983, 422476-2479 9. Hajjar DP, Fabricant CG, MinirJc CR, Fabricant J; V~rug in- dueed asheroscferasis: Herpes virus infectian aRers aorilc chpJasterol metabolism and acwmulatiert. Am J Pathd 1986. 12262-70 10. Graiten MT. MorCnaCabrai CF, Stamee VA, Qyet PE, Sdrr, san EB, Shurrnerly NE Gymrreg;alovirus inte:.bon is assvci- ated with cardiac aliognsft rejection and atherosdeross. JAMA 1989. 261:3581 -3566 11. MacDalafd K Rector TS, Braunlan EA, Coubo SH, Oifvari MT: Assnciabort of ooronary artery disesse in prdfac vz n,s- plarrt recpidlta with cytorneqaloviru,s in(eolfon. Am J Patd 19®, 64:358~fi2 12. Frerrcal N. Schirtner EC, Wyan LS. Katso(am G, Raftrnan I, Darevsch RM, June CH- I3olalion of a new herpesvirus from human CD4T calls. Prx Nat Aced Sct U S A 1990, 87:748-752 13. Gyortcey F, Mehnic-h JL, Gulnn GA, Gyorfcey P, DeBakey ME Herpes viridae in t116 pndodlelial and srrtoom rnuccJe cclls of the proximal aorta of atheroscttrocis parients. Exp Mot Padhol 1 %4, 40:328-339 14. Bendtt EP, B2rrotrT, McCa:fgal JK: Yrtusas k+dhe Qpoiogy of alheroscWosis. Proc Nat Aced Sci US4 19w, 60:6386-- 638G 15. Melnick JL Petrie BL, Dreearrw GR. Burek J, McCdk~m Cii, Debakey ME: Cyton*9alcvirus antigen within human anarial $mooth rtnx.cle cel~. Lzncet 19B3, 2,644-6d7 16. Petrie BL Melhicfc JL Adarn E, Burek J, McColkm CH, De• 8akey ME Nudefc acid sequence of cytom®gafovirus in ealle cultured from human atterSal tissue. J Infecx Dis 1987, 155:1513-159 17. Hendricfcs MGR, Sal'vnens MMM. Vanbavetl CPA, Brupge- men CA; High prevaler+ae of latendy present cyUortegaiov`- rus in artenal walls of patierus suffering from prade III amernsderosis, Am J Pytiol 1Si90. 136,23-28 18. Yamashlrora HM, Ghosh L Yang A, f3obertson AL• Herpes viridae in the coronary arttries arxJ aorm of young traume vir,>mC Am J Paihd 1968, 130:71-79 19. Karler RJ, lotzo RV, Ztie Z, Kefalides NA; Inhibitidl of pra teogyoan synthesis in humfn endothelial oells aRer infncvon wittt f-fSV type-1, in vttro. Am J Respir Cef! Moi Bid t990. 2:d23.A31 20. Hgar DP, Fnfcone OJ, Fabricant CJ. Fabricant J: Attered cholestetd ester cycle is assoCiated vrith ppid accsmxuiiatian in h.rpssvirius irlfected avian arter'sal srnooWt muscle cells. J Bid Chem 1985, 260;6124-8128 21. Hafyar OP; Herpetviruc infection prevents activation af cycs plasrnie chd@yto~A oCtarase in arv~ial smooRt rrusc{a cells. J Biol Cttem 1986, 261:7611-7614 22. Hajjar DP, Pomerantz KB, Falcor+e DJ, Weksler B8, Grant Ak Herpes simppex virus irfttien in human arteriat cells: Impticatioru in ahcnsckrosie. J CGn Invest 1967, 80:1317- 1321 23. Hejar DP, N'dholron AC. HaDar KA, Sando GN. Summers SO: Deaeased rtmseriger RNA transia6on in harpesvirus- infeCted zrtnrial cells: EUcta on cholecteM ester hydolese, Prpc Nat Acad Sci U S A 1989, 86:3366-.'i370 24. Vertxlkrlri GM: ProinttaRr, natory and procoagulant effects of herpes simpiex infectbn on human endotfletum. 81ood Cells 1990, 16:209-216 25. Nahmies A, Jocey K Ep'rd~ of nerpes sirrtp{ex virus 1 an0 2. Viral lydectiorts d Humarx-Zpidermology arsd Conmoi. Edited by AS Evans. New York Plerxtm MediCat Book Company, 1978, pp 253-271 26. Rooney JP Epiderriology of herpes sirnplex, Herpes S"m- pkxYrus Infectitn: B'ioioQy, TreaDnent and Prev®ntion. Ann InOem Med 1993, 1ffl:404-419 27. Johrson RE Nahmias PJ, Magder (S. Lee FK, Sroolcs CA Srovden MA: A seroepidemlakglc survey of the prava- lerica of herpes simplex virue type 2 infecvon in the Unirad Sabc. N Engl J Med 1986. 321:7-12 28. t',orden T, Gartia?almieri MR, Kagon A, Kannel WB, ScMff- man J: Ofitererces in rmrcnary heart diseate in Fruning- ham, Hondulu and Puerto Rica J Chrfln pis 197a, 27:323- 3" 29. Adarn E, Meln'cc Jt, Probesfi.dd JL, Peo'ie BL Burtk J, Biilay KA, McCdlun CH, DeBakef+ ME Higtt letirels of cy- tarncpabvirus antibody in patiertts requiring vasaufv sur- gery for aftletoeGerosic lancat 1987. 2:291-293 30. Havlic RJ, Blecfcwekier WC, Kasbw R, Casielfi W: UnrktfY a 4 0 4 4 I I I I I I I I I I I 1 I C1 ' .+.W ~' . I

I I I I I I ! ms na ro- on 30, od r I t I I I 3 of )od nis ind I asaociation be~ clinicaliy eppareni herpas-+inri infocr don and cfxonary inddonoe at okier apes: The Frirringhzm Heart Study. ArtlrioxlGraCia 1489, 8:877-880 31. MacGrega RR, Priedrtlan HM, Macarak EJ, Kefalfdes Nlt Yrus infocdon of endott+elial cells irr.r.asas qranulocyte ad- h.ranw. J Chn Invesc 1960. fi5:1468-1a77 32, Frierirnan HM, Manrik EJ, MaaGregor RR, Wolfe J, KeFal- ides NA Vinis inF.ction of endothelial ee{La. J Irtfect Dis 1966, 143:26&-.279 33. Ho 00, Rota TR, Andraws CA Ffrr,dh MS: Replicalion of human cytomegnlovirus in .ndothaial cNls. J Infect Dis 1966, 150,956-.957 34. TumiloMcz JJ, Gawlik ME, PaAell BB• Tronron JJ: RepFica- Con of cytomegabvinu in human arteriaf smooth muede cells. J Vi rol 1985. 56:633-W 35. Sydiskia RJ, Roznan 8: Prfysornas and protein synthesis in calls infeGeC with a DNA virus. Scivnra 1966, 153:76-78 36. F.nwicJc ML Clark J, Earty and delayed shut oft of host prorein synchasit in eells infected with herpes sirrplWc virus. J G.n triroll fl83, 61:121-125 37. Kefelidee NA, Laie Z Hcrp.e =implsz vinu suppressan of humen endothetlal matr6c protain syntttlesis ia independerrt of viral protain syrtthesis. Lab Irw~t 1986, 55;328-136 38. Lonoon FS, Broycer JM, tiaie Z Kefatdee NA: Supprassion of hoat mRNA in human srrmth musch calls by a virion compatrxit faotor in herpes simplex virua type 1. Lab Invost 1990, 621 @r9-145 39, Nishiioka Y, 5ifversroein S: Degradntlon o/ celfular mRNA dur- ing infectian by herpes simplex vins. Proo Nat Acad Sc! USA 1977, 7423742374 40. KworxJ AD, Kruper A Frerkai N; Herpes simplez virus vi- rion hoat ahutoff fwCtion. J Vird 1988. 62912-921 41. Paterson JC, Cotiraf GE Erperirrpntal eoronary scieerosis: IIf. Lyrr+pfnmatasis as a causo of coronary scierosis in chickens. Atrh Pffittd 1950, 49:69p.•707 42. Gibbs CP, NaZer'san K, Velixr LF, Kung HJ: Fsaip'vo ho- mology exists b@tween {Narek disaase herposvirus and its • vaccine viruC, herpesvirua of turkeys. Proc Nat Arzd SrJ U S A 1984, 81:33E5-3,369 43. Dudding L Hashsf S. Clairk BD, Auron PE, Sporn S, HuanQ ES; Cytomegaiovirus infecdon stimulate5 expresion of monocyte associated mediazor ganas. J Irnmunol 19e9, 143:3343•3362 44. Kdtiase M, Horrifsen-DeStefano D, May LT. Vcak J, Sah- gai PB: Induction of grinl.rhron by tvrer necrosis facax. a homeostabc m.chanism in rhQ Contrd of cell prdiferatial. Cep 19A6. 45:656~ 45. Wortp GHW, Gaeddd DY: Tunor necrosis faotors n and ~ inhibit vitus replication and synerfliza with ~tprf.r~. Na- tuM 1986, $Z3:819-~ 46 EGr,Qin OR. Hajar DP: Evidalce for CytaWne rt9ulabon of chof.s[erd metabolism in hetpesvinia-infected arterial cells by the lipnxygonssp padlway, J Upid Res 1990. 31 c99- 306 47, Ishiba9tr S. IrwbaT. 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