Букринская А.Г., Жданов В.М. Молекулярные основы патогенности вирусов

C0BHpycoB, B HIaCTH0CTH pecnttpaTOpH0-CHIII!HTH3.ilbH0ro BHpy­

ca HCMKT03

lJCM c J1PYrHM11 .11e11T11B11pycaMH, K noJ.LCCMe1"ICTBY K0T0pb!X 0HH 0TH0C5JI'CH, II C J(PYl'IIMII pCTj)OlrnpycaMH. O; H3KO CX0JICTB0 J13HHoii O0JIBCT!l C mrpyrnM K0pH, J(pyr11M napaMHKC0B11py­ C0M, 0fj)3HH4JIB3eTC51 JlliWb TpttneITTHJI0M (f)eH - X- fJJJI. Pa3JIWIHH Me)KJ!Y CaTHHB0n napaMuKcosupycaMn 33KJJI0lfaJOTCH T3K:li{e B TOM, 4T0 yKa3aHH0MY TpttnenTH/lY, C K0Toporo H3- '-JHHaI0TC51o6ur_ue nocJJe,AoBaTeJJb H0CTH, npc,uwecTBYIOT 7 0CT3T­ K0B rttJ(pocpo6HI,JX 3MIIH0KHCJI0T, K0T0j)bie B3j)bHpy,or y pa3Hb!X H30JUIT0B BHpyca H C,ll,83 JJH M0fYT HTpaTb KaKylO-T0 ])0JJb

B cmrn.HHH. TTo-BH]lHMOMV, neTI'fllJJ, CJl!UlHHH HC 065!33TCJJbH0 J10Jlllie11 61,n1, K0Hll.CBbJM 3eO6n3I3JC1cTH1M0pCC1

5eJJOI< C.11115lHIHI BI14 06.llD}l<lCT Bb!COKOl-1 3KTHDH0CTbI0 H BbJ3hIBae-r p3poJl,1 np01lccrow cC3cJ1H51HHc BHpycHoii 060110T1K11 C KJlCTOtIHOH MeM6panoli; 2) C'JIJl5JllHC C0CC)lHHX ytJ3CTK0B KJlC­ TOtIHOH MCM6paHbI; 3) CJ1!15lHHC 1rneT0'fHblX MCM6paH C0CC)lHHX KJleT0K. floCJIC/lHHH npouecc npHB0.ll.HT K o6pa30B3HHJO MH0fD.ll.ll.CpHblX KJICT0K - CHHll.lITHCB, HTI<OT0pble BK,1JOtJ3JOTC51 .LI.C­ CHTKH H .LI.3>Ke C0THII Jlf !M(pOUHTOB. KJJeTKII, BX0,llHIUHe B cocran CHHUHTH51, 06pet1eHbl na rnoe.nb; 0HH HC crroco6Hbl K .ll.C.IICHH.EO H HX )l{H3HCCITOC06HOCTb He npeBbUlJaeT 3-7 )lHeti. O6pa3o­ B3Hl1C CHHUIITHH 51BJIHCTC51 OJI.HOK 1!3 0Cll0BHblX np!!tillH ru6e.'1H HMMYH0UHT0B, KoropaH H3X0,AHTC51 B K0ppeJJHUHH C 9KC­ npecc11e11 6e.11KoB env Ha K.11eroCrnoi:r rroBepxH0CTH.

B C0CT3B CHHIUITIIH BX0Jl51T He T0JlbK0 3apa2KeHHhie BHpy­ C0M JIHMlpOll.HTbl, X0T51 C HllX 1-1aBrnHaeTC5l o6pa30BaHHe CHH­ IJJITHH. JlocTaro•rno KouraKTa 3apa)l{eJrnoro J1HMcpou1na c 11e3apa)l<eHHbJM, llT06bJ Bbl383Tb fi])0I.(CCC CJ1HflHH51, BCJJCJJ,CTBHC

9Toro 13 C0CT3B CHHUHTf151 BKJIIQlJ3I0TC51 H He3apa2KeHHblC T4+-KJ1CTKH [Joffe lB1br1al., oe0KI1a01.3THM M0llieT o6'b5JCHHTb CH

MacconaH rn6em, T4-J1Hl\1Cj:>011.11ron rrpa 11aJ111tmH e,nHHl1tIHbIX. 3apa)l.{CHI-IblXK.1ICT0K, npHB0.ll.5lJUi:lflK R03HHKH0BCIHIIO C0CT051mrn IIMMYHOJl.et\rnunra. MoHOIUffbl Tal.OKe MoryT BX0JtHTh R co­ CTaB CHHl\11.TlUI,0,ll,H3K0 Ollll ropa3).t0 MCHbTTIC llYBCTBHTCJlbllbl K B11pycy, t]CM T4-KJJCTKH. II Ha IIX nosepxH0CTII B MeHJ,IJlCH

HCTB

cTerremr rrpe,rr_cTaBJJeHhI M0JJeKyJ1b1 T4-peueTITopa [Clapham P.

et aT0HBaOpb1T3

B KYJlhTypax JHtMcpouinapHblX KJJCT0K BHpyc Bbl3bIBaeT 06pasoBaHIIC CIIMTIJ13CT0B ABYX THTI0B: rHraHTCK!fX MH0f0HAepHhlX KJICT0K, II0HBJJHIOJUHXCH Ha 10-14-ft ,IJ,CHh TI0CJle sapa)Ke­ HH51, H MC,lJ,JleHH0 pa3BHBaJOIUHXC51 MCJJKHX CHIIIUlTiiaJlhilhlX rro­ JieH. CmmaromaH aKTHBH0CTh pa3HblX rrITaMM0B M0)KeT 3Ha­ 'fHTe.!II1IO Bapb!tpoBaTb. OJLHH K,JI0Hbl BbI3blBaJ0T IrnTeHCilBH0e o6pa30BaJIHe CHHUHTHH, ,n_pyrne - rn6eJib JIHMq:>OUHTOB B oc­ H0BH0M sa Cl.JCT UHT0JIHTH'-JeCK0r0,nefICTBHH H ,IJ,eCTpyKIVI!f OTl(CJTbHblX K,iICT0K II o6Jia}L3IOT CJTa6011 C,IIHBaJOmei:\ aKTHB­ H0CTblO, TpeThll 0Ka3bJBaJ0T CJJa6oe l{HT0JIIITH4CCK0e ,n_e1'1cTBHe na .TJHivJ(pOIUITbl. CTa6HJlbHOCTb 3THX rrpH3HaK0B CBHJJ,eTC,ilb­ CTByeT 0 reHCTliIICCKOi:\ sarrporpaMMHpoBaIIH0CTH CBOHCTBa CHMllJiacToo6pa30Bc1HllH.

CymecrnyeT Koppe.rrnum1 MC)KJJ,y crroco6HOCTbIO IIlTaMM0B BJ:1q Bbl3b!Bc1Tb o6pa30Bc1HllC Cl1HUHTH51 H m,py.neHTH0CThIO. O6pasy10IIlllC CHHlUIT!fH IllTc1MMhI B 0CH0BH0M Bbl)J,C,JIH.'1HCb OT

corrpono,KJVJJIOCb yMeHhrneHneM HrncJTa CD4+-r<JTeToK. IlhaM­ MbI, He 06pasy10m11e CHIIILJITIHI, BblJI,emIJIHCb OT sapa)KeHHblX, HO He 60JJhHblX JIIIIL. Om1 Mel(JTCHH0 pocJIII B KY,llbType K.JieT0K, a B opra1111sMe He rrpoucxomrno yMe111,memrn HmcJTa CD41·-KJTe­ T0K [Tersme:tte pe3et al., oOpOMB3PasmPIIl.H Me)KJLY WTaMMaMH, o6pasyIOJUHMH H He 06pasy!01ILHMH CHil[(HTHH, M0ryT 6b!Tb o6yc.JJOBJJeHhl pa3HblMH llJHIHIHHclMH: 3aMeHoi1 0CTaTK0B aMHH0KIICJT0T, MOJI.1HPHKan11ei"1 r.nHKosr1.1mponamrn n gp41, H3MCHC­ HH.HMH 13 LTR. o6yCJIOB.mmaIOIUHMH pasny10 'IYBCTBHTe.T[bH0CTh IIITaMM0B K KJ1CT001Hb!M 3KTHB3T0paM TpaIICKpl!TIUHH, HC)'J,0C'!'a­ TO'IHOJ°I aKTIIBH0CTbI0 reHa tat, HCII0Jlh30BaH!leM ,n_pyroro K,lle­ T09H0ro penernopa eB.n,p.

flo cnoe11 3KTIIBH0CTII 6e./JOK gp4 I M0JKH0 cpaBHHTh C 6eJI­ KOM CJIHHHirn BHpyca CeH)laiL 0.1l.H3KO cyrn,eCTByeT II rrpuH­ UHnIIaJibH0e pc!3.IHI'ille: m1pyc Bbl3hJBaeT «CJJH51HHC 113BHe», T. e, 06pasosam1e CHHIUITHH B l!Cj)BbIC tJaCbl rroc.11e sapa­ )KClJHH K.!IeTOK 33 ClJCT ;'l,eiICTBirn 6eJII<a cmrnmrn B C0CTaBe n11pyc111,1x tJacnm, a BHq 11e crroco6eH K TaKoMy nrny cJTH.H­ HHH 1(3)Ke TIJ)H BbICOKOl1 MH0)KCCTBeHH0CTH HIHj)eKUHH H Bbl3bl­

B3CT «CJTH51HHe 113HYTJ)II» l!epes 24-36 q rroc.1e sapa:>KCHH.H

[Lifson cI3C13TTCH3aOpaM36JsiX3CH30HTC13hTK03aOpal361r3rr3yI3et al.,

oOpbMC3BosMO)KHO 3T0 ofrhHCHReTC51 n11oti KoHqiopMauHefi 6eJT­ Ka CJJHHHirn na II0BCpXH0CTII .!lI!MffJOIUITOB JI.Till )KC HC/J:()CTaT0lJ­ HblM K0JIII'ICCTB0M T4-Mo.neKy.r, 113 TI0BepXH0CTII 1IYBCTBHTCJ1b­ HhIX K.neToK; n K.nenrnx .,mr..Hpo6.1iacTOHJJ,HblX .TTHHHH '!CJJOBCKa

HT0e

'.J

•

Puc. 12. BapnaHTbI CJJl!IIHHH m1Mrpo1.urro11 np11 CrIHJC

l - npH B31iHM0,ll,C'1:CTDIHf nHpycuoii 'HlCTHUl,I C l{JICT01l!rhtMH MeM6paHaMH: 2 - npH UJaHMOJJ.C.fiCTUHH ).t,DYX ::rnpa>KCIIRh1X JlHM{})OU,HTOB, COJ1.Cp:acau.r.:Hx cnv 6eJlKli 1-1a nJt33M3TH'ICCJ(Oll MCMOpaue; 3 - npu B3RHMO,l\CHCTllltli 3apaJKen1rnro JlllM(pOlJ,HTa

CHeaapaJKCHHblM.

lfX K0Jnfl!eCTD0 rrp11Mem1eTCH OT 20 000 ,'.1.0 30 000 Ha KJJeTKY,

.9T0 lfHCJI0 ITO KpairHett Mepe B 2 pa3a MeHf,We, 1reM K0J!lflle­ CTB0 peuernopoB ,Il.Jrn BHpycoa rpmma, CcHAaii:, JJecoB CeMJJH­ KH. B03MO)KHO H ):r_pyroe o6b5fCHeIIHC 3T0ro q)eIIOMeHa: OH npo­ HCX0/l.HT 6Jiaro,II,ap.H oco6eHHOCTflM B3aHMOJJ,eikTBH5f 6eJJKa c.1HHHH.H BH4 c T4-pcue1nopaM11 m1MqJOUHT0B, npn 3T0M 06pas0Bam1c CIIHUHTHCB B0,lM0}KH0 npn K0HT3KTe IlOBcpxnocTei'i 33p,rn<e11Hb!X KJlCT0K, 110 He BHpycnbIX 113CTHU C HHMII (pHC. 12).

KaKHM nyTeM npoHHKaeT BI,·J.ll B 1rncTKH: nyTcM :>HA0UHT03a C IT0CJieJJ.YIOlUHM pH-33BHCHMb!M CJIIUIHHCM HJIH LJepe3 ITJl33M3TlflfCCKYIO MeM6paHy, MHHYH 3H,llOUHT03? HaxO,l)JITCfl JIH 6eJJOK 1-13 IT0BepXH0CTH nupyca D BKTHBH0H OpMe HJIH ero cpyI-IKUHOH3JlbH3H aKTHBH0CTb conpmi<CHa C H3MCHeH1!CM KOH· ¢opM31 HH MOJieKyJll,I llpII HH3KHX 3Ha'leHH5lX pH, K3K 31'0 npoHCX0}ll-:IT C reMaITJII0THHHH0M Irnpyca rpHnna? Ha 3TH Bonp0Cbl Il0JJY'ICHbl rrponrnopeqHBble 0TBeTf,l. )laHHbie 0 TOM, lfT0 n npHcyTcTBl-:IH XJJ0PHAa aMM0HHH cmne3 aupyc1n,1x 6e.n­ Koo B 3apa)KeHHbJX KJieTK3X fl0).J.3BJ!5!CTC51, a K0JIHLJeCTB0 CHH· 1 11n1eB K 5-My ,1.1uo noc.r1e 3apa)KeHJrn yMeHhrnaeTcJI, pacu.e­ HHBaIOTCfl KaK JJ:0K333TCJlbCTBa Heo6xOJ..(HMOCTH HH3KHX 3H3- lJe1-rnh pH ,1L,11.H npou_ecca cJrnmrnHBO BHYTPHK"1eT0'-IHbix BaKy0JJHX H np0IIHKH0BeHH.H BHpycttoro HYKJieoKaITCl-:1,ll_a B llH'fO· 1vca3MY [Maddon P. ct al., 1986]. O,a:naKo B03M0)KHbI ,ll,pyrne HapyrneHHfl KJJeT0'lH0f0 MeTa60Jll-13Ma, Bb!3B3HHbIC XJJ0PHJI.0M

MeHeHHIO K0Jrnqecrna HeHHTerpr1poBaHHOH qiopMbI ,LU IK, onpe-

183

,Li,emieMOH 11epe3 4 q TIOCJie 3apa2Keiurn KJ]eTOK JIHMcpo6JiaCTO· II,UHof, JIHHHH (VB). H11 xJiop11n aMMOHHH, HH XJiopoKBHH He BbI3bIB3JIH yMeHhllleHHe KOJIU'!eCTBa HeHHTerp11poBaHHOii: LLHK, He H3MeIIHJIOCb II 1IHCJIO CHHJJ)1THCB 11cpc3 48 lJ IIOCJ!e 3apa­ )l(CIIHH. CJieJ.I,OBaTeJibHO, BHpyc rrpoHHK3JI B KJieTKY B rrprrcyT­ CTBHI1 CJI36bIX OCHOI33HHH, lI IIH3KOe 3H3'!eirne pH He 6b!JIO

qeHHH pH ,UJIH rrpo1.1,ecca CJIHHHHH, XJIOpOKBHH H XJIOpH,U 3M· MOHHH yMeHbllI3IOT HHcpeKl.l,HOHHOCTb BHpyca 6oJiee 11eM Ha 90% [Helenius A. et al., 1982].

11pH 3JleKTpOHHO-MHKpOCKOllHIJeCKOM H3y11emrn 3apa2KeH­ HhlX KJieTOK (4 °C) BhlHBJieHo CJIHHHHe B11pycHwx 11acTH1.1, c rrJia3MaT1111ecKo!'i MeM6paHoi'i nprr Hei'iTpaJihHOM 3Ha11eHHH plI Y)l{e 11epe3 2 MHH ITOCJie no6aBJICHHH BHpyca K KJieTK3M. l1pH I-IH3KHX 3113'-!eHHHX pH (5,5) '-!3CTOT3 CJIHHHHH He yBeJIH'-IHB3· JI3Cb. 3TH )l,3HHb!e K3K 6y,UTO CilH,UCTeJibCTBYIOT O ITpOHHKHO· BeHHH BHpyca B KJICTKY 1Iepe3 f!J133M3TH1IeCKYIO MeM6paHy, MHHYH 3H,UOl.l,HT03, B YCJIOBHHX Hei'i.Tp3JibHOro 3H3'-JeHHH pH. yfa 3THX ,U3HHblX CJie,UyeT, '-ITO BI14 rrpOHHK3CT B KJieTKY ITO TaKoMy llie MexaHH3MY, KaK H BHpyc CeHnaii: 11 npyrne rrapa­ MHKCOBHpyc1,I, ero BbICOK03KTHBHblH 6eJIOK CJIHHHHH H3XO,UHT· CH B COCTaBe BHpycHOH '-13CTH].l,hl B cpyHKl.l,HOH3JlbHO 3KTHBHOH qiopMe lI He Tpe6yeT HH3KHX 3H3'-JeHHH pH ,UJIH H3MeHeHH5I KOHcpopMa1.1,11H. TeM He MeHee crroco6HocTb B114 HH,Uy1.1,Hpo­ B3Tb CJIHHHHe MCM6paH rrprr Heii:TpaJibHOM 3H31!eHHH pH ITO· 3BOJI5IeT rrpe,UITOJIO)KHTb, '-ITO ,U3)1{e ITPH 3H,UO].l,HT03C BHpyc rrpoHI1K3eT B ].l,HTOITJ133MY H3 3H,UOl.l,HT3pHbIX B3KYOJieH C He!'i­ TpaJibHbIM 3HaLJeHHeM pH. TaKoH ITYTb rrpoHHKHOBeHHH B KJieT­ KY 0llHC3H H3MH ,UJIH BHpyca ITaparpHITITa '-JeJI0BeKa THIT3 3, 6CJIOK KOT0poro CITOco6eH CJIHB3Tb MeM6paHhl ITPH HeHTp3Jib· HOM 3Haqel!HH pH. EcTb 3H3JIOrH ITO,U06Horo rryTH rrpOHHKHO­ BeHH5I B KJieTKy H cpenu peTpOBHpycoB. MbillIHHbIH peTpOBH· pyc T3Kllie Tpc6yeT HerrTpaJibHOro 3HaqeHHH pH [Portis J. ct al., 1985]. O,UH3KO aBTOpbl 1.1,HTHpyeMOH pa60Tbl MOrJIH He o6HapylliHTb 3H,UOl.l,HT03, IT0CKOJibKY KOHT3KT BHpyca C KJieT­ K3MH ITPOB0,UHJIH ITPH 4 °C, K0r,Ua ITpo1.1,ecc 3H,UOl.l,HT033 ITO,U3B· JieH. l1pH 3JieKTpOHHO·MHKpOCK0ITH'-!eCKHX HCCJie,UOB3HHHX ITPO· HHKHoBemrn B KJieTKY BHpyca rpHJJJJa Mb! o6Hapy2KHJIH, 11To nprr 37 °C BHpyc ITOIJa,UaeT B KJieTIrn KYJibTYPbI TKaHH rryTeM 9H,UOl.l,HT03a, a ITPH 4 °C - ITYTCM CJIHHHHH C ITJI33M3TH'-!e­ CKOH MeM6paHOH KJieTKH [AHHCHMOBa 3. 11 np., 1984]. l1ptt HCllOJib30B3HHH 3JieKTpOHHOH MHKp0CKOITHH 33pa2KeHHOH B114 JIHHHH KJieTOK 6hlJIH OITHC3Hhl o6a nyTH rrpOHHKH0BeHHH BH· pycHbIX qacT111.1, BI14 B KJieTKH - pe1.1,enTopHb1I'i 3H,UOl.l,HT03 rr

184

185

(jHILJecKoe CBH3bmai-rne HYKJ1eoKancHJJ.HbJX 6eJ1KoB c PHK,

IT0·BH,ll.HM0MY, o6ycJIOBJICIIO K0HCepBaTHBIIblMH 0CTaTKaMJI UH· CTeHHa B 6oKce Unc - fnc [Gorelik pHaCbHal., OHbbIo,

Bnosb o6pa3oBaIIHaH )JJIK noHBJrneTCH B UHTorrJia3Me H 6blCTpo TpancnopnipyeTCH B 51J(p0, npeBpaIIta5ICh TaM B KO.'Ib· 1 eBy10 cpopMy. Onpe,neJiennaH qJpaKUHH Tn6, HHTerpHpyeT c xpoMOCOMOI°I, HO 3HalJ.llTCJII,JlaH lJ.3CTb MOJJeKyJI OCTaeTCH B qJopMe HeHI-ITerpnpoBaHHbIXoaTBBepoHTHO, III1Terpa1 1rn HB· JIHCTCH JIHMHTHpy101UIIM <j)aKTOj)OM, onpe,ll,CJIHH)JUHM Slq)qJCK· TiiBHOCTb TpaHCKpHITUHH. TipH aKTHBaJJ,HH np0B11pyca rrpo­ HCX0,Ll,HT 3KcrrpeccHH BHpycttblX renoB, c6opKa H nop1K0Ba1me BH))YCHblX HIaCTHI . O,Ll,HaKO p1epe3 0IeKIHoTBo6pasyeTC5l ,Ll,0CTa­ T0l{l!Oe lJ.lICJIO M0JICKYJI gp120, lJT06bl 3a6JIOKH))OB3Tb peuerr­ T0p CD4 11a KJieT01rnoii noBepxaoCTH n rrpe,nornpaTIITb B03· M0)KH0CTh cyuep1rn<i)CKUHli, II HIIqJCKIUIOHHhll Irrpouecc 3aTy­ xaeT. Oco6emwcTbfO BI14-m1qJeK1t1rn, OTJIIItrammeii ee OT JJ.pyrnx peTp0BHpyCHb!X HHqJCKUHfI, HBJIHeTCH HaKOITJICHHe B 51,Il·

pe 60JiblI!HX K0JIHl!eCTB HCIIHTerpHpoBaHHOH JIHIICHHOH II 3KCTpa­ XpOMOCOMIIOH KOJibllCBOH BirpycttoA a3l6,X6Ui,HB,ct al., KHbHn

Pauza Jop,Galindo J., OHbHrI,9TH M0JICKYJibI penmrunpy10Tcr1 HC3aBHCI!M0 OT pellJIHKaI Hli mnerpnposamwro II{)OBHpyca. TaKa51 <popMa HCHHTerpnpoBaHHbIX Hl1, xapaKTepHa JJ.JIH MO· HOUHT0B, B K0TOj)blX ycTaHaBJIHBaeTCH oco6bllI TI!Il B33HM00T· HOlUCHHH C BHJ)YCHbIM reHoMOM. Tio-BH,IlHMOMY, B MOHOIVITax HHTerpauHH Bnpyctt011 e3l6,c xpoMocoMoi\ Boo6rne He npo­ ncxo,Ll,HT, n 3KCTpaxpoMocoMHaH e3l6,JJ.JIIITCJibHoe speMH nep­ CHCTnpyeT B KJICT0aIll0M 51)1,pe, Ile npml0/J.51 K pa3pyrneHHJO KJ1CTKII. Tairnfi Hl6, npIIcymH 11eo61,1Hrnb1e tieprbI: ee ,nJIHHa 6oJibllle, tieM ,nmrna BHpycHoro reHoMa, BHpycHhie nocJre,noBa­ TCJibH0CTH paccpe,noT0lJ.Cllbl no ,Ll,J1HIIC M0JICKYJlbl, 3TH qJOj)Mbl Hl6, CTa6lwbHbl n qiyHKUH01rnpy10T KaK aBT0H0MHbie pernrn­ K0Hbl. Bo3M02Klla caM0HHTerpauH51 MOJICKYJI, OCHOBaHH35l Ha mnpareIJHOti peKOM6Hl-IaJ\Ifll. O6pa30BaHHe TaKHX <jlopM o6yc­ JIOBJIHBaeT neprncTemu110 B11pyc1-1oii e3l6,B MOH0UHTax II MaKpO(}Jarax ll npeBpamaeT 3Tll l<JICTKH B )l,JIHTCJ!bH0 CYlllC· crny10111,HI°l pesepByap BHpyca B opramnMe [Pauza OTHHGalin­ do MopHO bHIB,MonorlHTbI H MaKpoqiarn 11Me10T MeHbIIIee prncJio M0J1CKY.rI peuenTopa CD4 Ha cBoeii rroBepxnocTH no cpaBHC· HHI0 c T4-,riIIM(po1 1ITaMIL I-IecMoTpH na 'IYBCTBHTCJibH0CTJ;, K BHpycy, mrn ne norn6aIOT rrpH ero penpo,nyKUHH n 06ecneprn­

BaIOT B03M02KH0CTb nepcHCTHj)0BaH!l5l Bllpyca B opraHII3MC [Laurence epHBMHbby,Levy cBaHcHbbC,Pauza C. et al., CHbbI0,

B KJleTKax co,nep)KIITCH 60.lhlIIOC I{OJllilieCTB0 HC3pCJib!X BH­ pycHhIX lJaCTHIJ. BO BHYTJ)HKJ1CT0p!Hh!X BaKy0JIHX H He3Haern­ TeJibII0e K0JIHCieCTBO BHpycHI,lX aHTilfCH0B Ha noBepXHOCTII

186

KJieToK [Gendelnrnn H. ct al., 1988]. 3T!1 oco6eHHOCTii onpe­ JlE\'HIIOT cnoco6HOCTh BHpyca rj)opMHpOB3Tb JJaTeHTHYI0 J,[11- (peKJl,HIO. O;1_uaKo np0BIIpyc M0}l(eT aKTHBllpoBaTbCH, npII 3T0M np011CX0}l,IIT ero Tpa11rnpHHUllH, B pesym.,TaTe CJI0)l{HhJX npo­ ueccoB c1u1aiic1rnra 06pasy10TCH MPHK, CIIHTes11py10TCH 6eJ1- KH-rrpe)lruecrneHHHKH, Hx 11pouccc1111r npHB0JJ,HT K 06pasona1u110 tpyHKUIIOH3JlbHblX 6eJIKOB, npoHCX0)lHT c6op1<a BHpH0H0B II BblX0,IJ, HX H3 KJJCTim nyTeM 110l!K0B3I-IHH.3TOT npouecc HMe­ e'f B3pb1B006pa3Hblff xap3KTCp: :-ia 5 MHII 0;1,rrn KJJeTKa M0)KCT 11H.11.yu,11pcman, ;1,0 5000 B11pyc!Il,1x •WCTIIIL Ti.mue TCMnb1 He cso1k-rncHHbI HH 0)1,uoi-i ;1,pyroh 1rnpyc1101i 11uctie1<uuH.

KJuo11eBbIM Bo11pocoM 11aToreuc3a B114-1mcpe1<1ll-JH HBJJH­ fOTCH TIJ)ll'IIIHLI, llJ)HB0/1,}lllJJ[(' K aKTIIB/JU,1!11 ll[)0Bttpyca. TaKHX IIPfJT!Hll HeCK0JibK0. OcHOBHa}J CB513aHa C 3KTHBaUHCfl JlllM(j)O­ UJITa, CO)l,ej))K3!Jlero npoB11pyc. I1oK051UlHeCH JIHM(J)0U,l1Tbl He­ nepMHCCHBHLI K Bl11.J 6J1aroJJ,ap51 0TCYTCTBH!O KJICT011HblX (j)aK­ T0pOB, HeO0XOJlHMblX )lJl5I CHHTe3a TI0JJ!-IOpasMepHbIXM0JJCKYJJ ,UHK-11p0B11pyca 11 ero HHTcrpauuu c KJJCT0'IHbIM reHoMoM; B TI0K0Hlll,HXCH JlHMQ)O!_llfTaX MOJKCT )lJ1!1TeJJbl-!Oe BpCMH naxo­

JlHTbOI ueu1-1Tcrp11poBaHHbliJ re1101v1 [Zac.:k J. ct al., 1988; Cul­ len B., Green W., 1989]. AK'nmar.urn T-mll\Hj:lor HTOB pe3KO

MCHHeT ClITyau.1110. AKTl!Ball,JJH in vitro npHB0l(HT K npoJJmpcpa- 11,I-IH KJICT0K II IIp0JlYKIlllll IJ111]>CKU;I-IOIIHOr0 BHpycHoro IT0T0M­ CTBa. O)J,llaKo, clKTllllHp0BilllllOC C0CTOHHHC BH0Bb CMCH51CTC51 C0CT0HIIIICM ll01(051 II 3T0T IIC!)H0.11. couna.uaeT co BTopott J1a­ TeHTHOH (pasofI IIml>eKIUIH, Ho ua 3T0T pa3 11p11 HaJJHlJHH 11H­ TerpHpoBaH1-1oro nponttpyca. IIocJJcJJ,y1oulaH pcaKTHBaJ(IIH Ta­ KHX KJ1CT0K pa3Jlfi11Hb!MH cpaKTopaMH Bbl3b!BclCT peaKT1IBa11,mo «M0JJ4alll.ero» nporrnpyca Bl11.J.

ct>aKTOpaMH, aKTHBHpy10lll.HMH np0B11pyc B JT0K0Hlll.HXCH T-JJHM(porvnax, HBJ1HIOTC51 aHTHl'CHbl, UHTOIU!Hbl, KJJeT0'IHblC -rpaucKpHTI!UiOHHhlC (j)aKTOpbl, co6cTBeHHblC -rpaHC3KTHB3T0J)bl II reTCJ)0JIOrHlJCCKHC TpaHcaKTJ-IB3T0pbl, 06pa3y10m11eCH npH sapax<eHHH T-JJ11McjJ01uIT0B .upyrnMH BupycaMH. KJJeTO'IHbre TpaHCKp!-InUHOHHblC (j)aKTOpbl, aKTHBHPYI0UJ.HenpoBHpyc, Mory-t noc-romrno np11cyTCTB0BaTb B KJJerne (Spl, TFIID H Jlp.) JJ1160 fl0HBJJ51TbCH B pe3yJlbT3Te HHJlYKUHH .upyrHMH KJJCT011Hb1MH cpaKTopaMH (NFlxB, NFAT-1 H .up.). MHorne .uaHHbie yrrn3L>IBaJOT Jia TO, 1IT0 3KTHB3UHH npoB11pyca mo6b!MH areH'raMii oCylUCCTB.llHCTCH JJHlllb npH nocpc.ucrnc KJICTO'IHblX rrpa11c­ KJ)llnllH0HHblX cjrnKTOJ)OB (cxeMa 6)' np11 .3T0M 3Ha1IHTCJlbH3H p0Jlb 0TB0)lHTC51 CTa6HJ1bHOMY KJJCT01IH0My (j)aKTOpy TpaHc­ Kj)HTII.!Jlll Sp1 [Harrich D. et al., 1989]. BeJIOK CBH3bIBaCTCH c 3 06J1acrnMtt LTR rrp0B11pyca H cTnMyJmpyeT CBH3blBaHHc 6eJIKa Tat c o6JiaCTblO TAR. npcJlnOJJara10T, tJTo Spl oTBeT-

187

R U5 33U3 R

crneH sa B3al!MOJ1.eiknrne c pHKTBcex CB.H3brna1olll,IIXCH c Heii 6e.'JKOB II 06pasy1011\HHC5! Tp3HCKp11IUUIOIIHblfl K0Mf!JieKC BameH ,LI.Jrn aKTHBal\HH LTR 6eJJKOM Tat.

Oco6euno mnepcceH HHJJ.YI\Hp0Ba11H.1,rfi cjJaKrnp Tpa11cKp1m­ LOJJI NF-xB. CBoe HasBaHIIe 6cJJOK noJJy'IHJJ B CBH3H c xoMn• JICKCllp0BaHIICM B B·KJ1CTK3X C o6JiaCTblO ycHJJHTCJrn reHa, K0/JJipy1011(ero JJCI'KYIO ]\Cl!b lIMMYHOI'Jlo6ymma, TclK H33bIBae­ M0ro %B. Be,10K o6napy)l{CH B HJJ.CJ)HbIX 3KCTpaKTax T-.HHM· cjJO]\HTOB II MaKpocj)aroB, 3KTHBHpoBal!HbIX HMMYH0CTHMyJrn­

TopaMH H IIMMYH0l'CH3MH, OH 0TCYTCTB0BaJI B n0K0.Hlll,IIXC.H

.rrnMtj)OIOITax [Lcnardo XKHlBaltfmore JTplMbybYIlNF-xB HHJJ.Y· lUrpyeT 3KCIIpeccmo rCH0B ,ll.pyrHX 1U!T0Kl1H0B H caM IIH,LI.YI(II· pyeTCH I(HT0KHHaMH, HanpHMep KTHpI[Osborn L. ct al., abablpH 3TO HpKHfl Tlj)HMCp ayT0CTHMy.1rnpy1omero pcrymnopH0I'0 .9ql· Q)CKTa. IIpH H0pMaJlb!I0M l!MMYHH0M 0TBCTC .9KCnpecCH.H NF-xB B T-KJJeT1rnx BbI3bmaeT aJ{THBllpoBamre TpaHcKpHnl\HIJ onpC,ll,CJICHHbIX KJ]CT0'IHblX reH0B, perym1pyIOlll,HX npoJJHtj)epa•

LI.HID T-KJJCTOK, BKJIIOtJa,1 60OnClH a-cy6'hC,ll,HHlll Y peuemopa 601oCl[Hoyos B. ct al., I bybYBelMo,ll,CJib JJ.,JI.H 1nyqcmrn MexaHH3-

Ma 3KTI!Ila]\HH np0BHpyca c60Bl9TIIM 6eJIKOM 6blJJa C03)].a!Ia

188

nyreM Tp,:!HC(j)CKI].flll T-JIHM{j)Oll11TOI3 I1Jla3MJIJI.OH, CO/lep;trnrueii o6JI3CTH yc1UUITCJrn H l!JJOMOT0pa Bl14, CBH3aHHhJX C reH0M CAT. NF-xB «y:m,IBaJ1» c1JcruHfrn 1 1ec1(y10 110cJ1e,uonaTeJ1hH0CTh ycHJJJITc.rrn B114. CBH3hIBaHIIC 6c.nKa c ycIJJlllTCJ1eM np1rno­ }JJIJI0 K 50-KpaTHOMY CTHMYJIHJJ0Balll!I0 aKCllpCCCIIH IIJJ0BHpyca [Nabel G., Baltimore D., 1987j. YcHJlHTCJlh B cocTaBe LTR npom1pyca B114 CO,ll,CJJMHT /].Be o6JJaCTH CBH3b!B3Hll5f C NF-xB, KOTOJJbIC 3Ha'rnTeJII,H0 Bapb11py10T B K.'lCTKax pa3HhlX JIIIM<pOH,ll,llblX JUIIHH.

JlaTCHTIHlH CTa)].llH BI14-11mpcKUJ!H B II0K0JUUJ!XCH T-JllIM­ (j)OllJITax MO}KCT 6LITb npeo;ioJJC]Ja nyTCM ll!I)J,YKUIHI CHHTC3a NF-xB n nepexo,lla JHIMcjio1111Ta B aKTHBHpoBa1111oe cocT0HHHe, a areHThI, IIH/l,YUII]JYI0UJ.lle 06paJona11He NF-KB B MOH0UH­ TapHoii JIHHl!ll KJICT0K, co,uep.tKaru11x Bl14 np0BHpyc, pe3K0 CTHMyJI11py10T np0JiYKUHJ0 B114 [Griffin G. et al., 1989]. O,n­ HaKo B CTHMYJil!ponaHHblX JIHMq_JOUHTaX 6eJIOK BC 6hIJI HC06X0)J,HM }l)Ul peilJIHKaUirn BI14 H q:>yIIKUUH TpaHC3KTHBaTopoB

MOI'JJH Bb!IlO.lIHHTb JJ.pynic K,IJeT01-IHhlC (paKTOpbl TpaHCKf)HIIUHH [Leonard J. ct al., 1989].

Pery.irn[(us, penJJMKau1m 811 11. B pe3yJILTaTe KOM6mmpo­ na1-moro/].CHCTIHIH CTa6IJJlbl!l,JX II IJI-IAYUHpoBa!l!h!X KJICT01IHhlX (j)aKTOJJOB TpaHCKp1111um1 B a1nmrnp0Bal1Hb!X T-JIIlMqJOUIITax rrpoHcxo,ll,HT TpaHCK[HlllUHH upom1pyca BH4. BHa,rnJie 3KC­ npeccr1pyeTcH 11yJ1 ;mmKJJ.bI cIJJJa1ic11pouam1Lrx MOJieKyJr MPHI(, HCCYIUHX JHHj1opMaumo C peryJIHTOJJHblX reH0B tat, rev ll nef [Malim M. ct al., 1989]. 3aTeM peryJrnTOpHbri'1 6eJIOK Rev Bbl3bIBaeT rrepeX0JJ. OT pa1-rndi K IT03JJJ!CI1 l1la3e 9KCIIpecc1m BHJ)YCHblX reHOB, K0r)l.a llj)CHMYIUCCTBCH!iO Cl!IITC3HJ)Y!OTCH CTJJYKTYPHh1e mrpycnhie 6e.r1K11. TTo,'1HOpa3MepHaH J1m1eiiHaH )l!II<, noHBJIHCTC51 1iepe3 4 11 IJOCJIC 3apa,Kemrn. CTpH 0AH0UHK­ JJOB011 IIHq)CKUHII KOJIJll!CCTB0 ee yuemtturnaeTCH K 12 q HHqJCK- 1 1111, a 3aTeM na,llaeT. B11pyccncumpw1ecKaH PHI( noHBJIHCTCH l[Cj)C3 12-16 'l IIOCJIC 3apa}KCHllH, '1Cpe3 24 q Ha1IHHaCTCH npoJJ.YKUHH m1pycm,1x qacTHil [Kim S. d al., 1989]. PeryJrn­ IJ.HH 9Kcnpecc1rn reHOB BHL! ocyruecTBJIHCTCH Ha CJI0)KH0M ypoBHe, KOTOf)bllf OTJIIl'HlCT JICHTHBHPYCbl OT peTpOBHpycon THHOB B u C II ttanoMmtaer perynmi.mo y ,IJ,HK BHpycoB. B pe11JI11KaT11BHoM umrne nou1e;i.m1x cy1u,eCTBY!OT pmIHH5l n ll03J].H515l <p33hl, 1<01',Qa CIIHTC3Hpy10TCH COOTBCTCTBelIHO pery­ JJ51TOplibIC H CTpyKrypHb!C irnpyCHblC 6eJlKH. PeryJIHUJUI ITO nmy )JJIK-co; eplliaIUHX m1pycoa, HanoMHHaromaH. Bl14, caoikrnerrna 11 mrpycy JieHK03a 1 ieJ10Be1rn HTLV-1. Ero Tpanc­ aKTHBaTop Tax, KaK H Tat, cnoco6cu sna•rnTe,11,Ho ycirnnBaTb TpaHCKpHIIUW0 BHpycHb!X rel!013. O)].HaKO, MCXaHl13M ,llCHCTBIUl Tax ,npyro11: npoHcXOJI.IIT aKTHBaum1 cneum}rnqecKHX KJJCT0LJ-

189

Hb!X cJia1nopoB TpaHCKp1murrn, H3MCHHJOl1JJIX 9KCnpeccmo K31< BHpyCHux, TaK II KJieT0'llfbIX reH0B [Leung I(., Nabel G. ,

1988). )lpyrofi TpancaKnmaTOp HTLV-1, rex, no a1rnJiornn c Rev ycHJllmaeT 3KCnpecCHlO HC TI0JIH0CTblO CllJI3HCHpOB3HHblX MPHK, K0,DJ1py1ou1,11x CTPYKTYPHLIC B11pyc1rne 6eJIKH. KaK H Rev, .9T0T 6eJJOK HBJrnCTCH <poccponp0Te11;1,0M 11 JI0KaJrn3ycTCH B H;-1,pbllllKax 3apa2KeHHblX KJICT0K, o6a 6eJIKa Il0,ll,aBJ15IlOT 9KC­ npeccmo ,ll,Ba2K,nh1 cr1.JiaflrnpoBaHHOl'i MPHK, KO,nHpy1onie11 CHHTC3 pery.nHT0pHbIX 6eJJKOB [Hidaka H. et al., 1988]. O,ll,Ha­ Ko Rev BH4-l He HHrn6HpyeT B TaKol'i creneHH 3Kcnpeccmo, KaK Rex, rro-BHJJJIM0MY, B CBH3H c TCM qTo npo,ll,OJ12KaeTcH .9KC­ npeccHH 0,il,H0f0 9K30Ha tat C o6pa30B3HHCM 0,ll,H0KpaTH0 cn.1aikupcrnamrnii MPHK, H 9Ta PHK Ko,n11pyeT rpy64aTb1i1 6eJJoK Tat, 06JJaJI,a10mHfl cpyHKUHOHaJ11:,11oii aKTHBH0CTbIO [Ma­ lirn M. et al., 1989].

HecMOTpH Ha cpyHKUHOH3JlbHY!O aHaJIOfll!O, reHhl rev fl rex l!C IIMelOT l'0M0JI0ril'mb!X ITOCJIC,ll,OBaTCJlbllOCTCH. 8 TO )KC Bpe­ MH Rex M02KeT 3aMeHHTh cpy11Kumo Rev B114 n «cnaCTH» penJJHKaI{HJO ,ll,erj)eKTHoro no rev npoBnpyca B114 [Rimsky L. et al., 1988], xorn Rev He M02KeT 33MeIUITb cpyHKfUIIO Rex B ,ll,ecpeKTHOM IllTaMMc HTLV-1. Bo3M02KHocTb 3aMeHHTb Rev 6eJJKOM Rex yKa31:,maeT Ha To, tIT0 o6a peryJrnTopHbIX 6eJJKa B3aHMOJI.eikTByJOT co CXO,ll,HbIMH cTpyKrypaMn PHK.

Ham1Hrne TaKoii pery.1HUHH 3Kcnpeccmr BHpycHbIX reH0B

Bl14 H CX0AHblX JJeHTHBHpycoB, a TaKlKe BHpyca JJCHK03a qe­ JI0BeKa HTLV-1 o6ycJIOBJJHBaeT cnoco6HocTb B11pycon BbI3BaTb JJaTeHTHY!O l!HqJel{JVIIO H 1136elliaTb pa3pylllemrn 3apa2KeHHbIX

KJ1eT0K HMMYHHh!MH MexallJJ3MaMH opraHH3Ma. Oco6eHHO HpK0

CTpaTernH Bupycnoro reHoMa npoHBJrneTcH B 06ecneH1eHHH

0blCTpOro nepexo,na .riaTeHTHOH Bl!pycuo:ii HHqieKUHH B aKTHB­ HY!O cpopMy C B3pb1B0Oil3CHbIM qiop1vrnpOB3HHeM BHpycHhlX qa­ CTHU, npn K0T0p0M YMCHI,maeTCH B03MO)KH0CTb 3qJcpeKTHBHOfO

HMMYHHOf0 OTBeTa.

Haxo,nHch BHYTPH 3apmKeHnoro HMMYH0UHTa, BHpyc orpa)K­

AeH OT He6Jrnronp1u1T11oro ACHCTBHH cpaKTOpOB ryMopaJJbH0l'0 HMMYHHTeTa. B TO )Ke BpeMH B C0CTaBe !10JI.BH2KHblX KJieTOK

MOH0JJJIT0B H MaKpocparoB m1pyc M02KCT Tpai1cnopTHp0BaTb­ C5I n JJio6yro TKaHb II 0T,ll,aJieHHbIC opraHbI, B TOM q11cJJe n UHC, MHHYH reMaT03HI(ecpaJIHl!ecKHH 6ap1,ep. B MOHOIIHTe perrJJHKa­ UHH B11pyca orpaHIFieI-rn, 0JI,H3K0 npH npOHHKH0BeHHH B TKaHb, rJI,e np0IICX0JI,HT C03peBaHI!C M0H0UHT3 ,ll,O MaKpocpara, penJ1II­ KaQHH B11pyca ycHJJHB3CTC5I. BHOBb o6pa30BaHHNe BHpycH e rracnU(bl Bbl3b!Ba!OT HapyllleHHe cpyHKUlUl KJieT0K, a H3MeHeH­ Ha5I II0)l BJJHHHHeM BHpyca ACHTeJJbHOCTb M3Kpo(para npHB0- )1.IIT K nonpe)K,neHHIO TKaHn. l1MeHHO TaKaH CHTyauHH CKJia-

190