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

,! IC0K3l1Ctt,U0B 06ycJ10BJ1eHa CHrHa.noM, ltaX0A5!lll,HMC5l B 06J1a­ CTI-I Me.iK.UY 5'-LTR H reHOM gag [ Lever A. et aapeT1989J.

nptt A0CTHmeHHH 3THMH K0M0JleKCBMH TTJ183MaTuqecKoA MeM6paHbl KJleTJ<H ocyru.ecTBJl5IeTCH caMoc6opKa BHyTpeHHJlX cTpyKTYP c o6pa3osa1111eM supyco110JJ,06HbIX 43CTHU.

OcTaeTC51 HeH3BeCTHblM, K3KllM o6pa30M npoHCX0AIIT Y3Ha­ BaIrne 6eJ1K3MH cep,ll,IleBIIHbl y•iaCTK0B llJJ33M3THlfCCK011 MeM6paHhl co BCTpoeHHhlMII 6c.nKaMJ! env. Bo3MOmHO, 3T0 ya11asa11ne np0HCX0JI,HT y)Ke noc.rrc CB5I3I,mamrn gagpol C MCM6pa1-10A B pe3yJJbTaTc TCKY'IC'CTII ,iJlUTHJ!,H0fO 6HCJJ051. Tipe;L­ lllCCTBCHHHK gag - pol 335IK0p11B3CTC5! B MCM6pa11e 6m.lfOA3p5! MttpHCTHJJHponmrnoMy N-Kon11y nrKAIUCcTncHHIIKa gag. llo-n11-

.UttM0MY, 3T0 C06bITHC HB,/JHCTC5! Kj)HTTl'ICCKHM Jl,JJH c6opKII BHpyc110A l(3CTHllbl, TT0CK0JlbKY IICMHpllCTll.llHponaHHblC M0JJe­ KYJlbl gag K ITJJ33MaTH4eCKOI°I MeM6paHc K.'leTKH HC rpaHcnop­ THPYIOTC51 n B c6opKe He ytiacmymr IRhec S., Hunter E., 1987; Schultz A., Rein apeT1989; Gottlinger H. ct al., 1989J. ]lJrn C3MOC60pKH He rpe6yeTCH npo-reo.'IHTHlICCK0ro nponec­ cmira gag: Myraum1 B KO.ll.Hpy10Iueii np0Tea3y 06.rracru, npe­ JL0TBpaI1IaKHlU!e npoTe0Jl!fTH•IecK0e Hapc3atrnc npCJI,llieCTBeH­ HHKa, He 6JIOKHpymT c6opKy cep,ri,uerrnm,I H TI0'IK0B3Hlle RH­ PYCHblX qacn11i [Dcclrnmhre M. ct al., 1989]. MyTa1um B 06J1aCTII rcHa, K0)1,11py1011leii K lllCYJJY cep,ru1cBHHbI (p24), He npenHTCTl3YJOT caMoc6opKc cmIpaJ1hHoro nyrrneoKanrn,na, K0ropbu'i C0Jlep)mIT reH0MHyI0 PHK [Gottlinger H. et al., 1989]. TaKHM o6pasoM, ¢opMnpoBantte HYKJle0KancHna He CB5!3aHo C ¢opM1IpOB3HHCM KOHYCOBH,ll,HOH cep,uuemHlbl. O,nuaKO np11 ,ne¢eKTe B 06J1acTH, K011,11py1on1ei-T p24, o6pa3Y!Olll.Hern Bttpno­ Hhl JIHllieHbl HHtpeKUHOHHOH 3KTIIBH0CTH, HeCM0TpH Ha H3JlH­ •rne K0HJJ,CHCl!p0BaHH0ro HyK.neoKanCHJla. Ha M0JleJlll ,ll,pyrux perpoBHpycoB (Mo-MuLV) noKasaHo, ,no p24 HaxoAHTCH B KoMnJJeKce c npoBHpycHoi-i JJ.HK KaK e l!HTon.na3Me, TaK H 13 H,npc 3apa)KCHHbIX KJlCT0K nepe,ll, mnerpauHeil:, a 0TCYTCTBHe p24 6JrOKttpye-r 06parny10 rpaHcKpImumo H HHTerpm1Hto npo­ Bttpyc1-1oii ,UHK [Gottlinger H. ct al., 1989].

Tipn KPHTHt1ecKof1 K0HUCHTpaunn M0J1e1<yJ1 env H gag B IIJJa3MaTWleCKOH MeM6paHe KJICTKH np0HCX0AHT HX B3alJM0AetICTBHe, 06ycJJOBJlCHHOe, 110-BH,llHM0MY, BblCOK011 CTeneHb JO aqJ{jHIHHOCTH gp4I K p17 H o6pa3oBaHHeM K0MnJieKca C HX Y43CTHCM; CB5!3b gp4I C p17 B C0CTaBe 3peJJOH BHpycHOH qa­ CTHU.bl fl0ATBep2K}1-aCT 3T0 npeJJ,Il0JJ0)Kelrne. BcJ1eJJ, 33 o6pa30B311HCM K0MllJJeKCa np0HCX0J],llT IT0eIK0B3HHe nnpycHhlX l!a­ CTIIU. C J{JlCTO'lHOll TI0BCpXH0CTll. 9TOT nponecc, 110-Ril}I,HM0MY, T3K)l{C CBH33H C acpqnrnHOCTb!O M0JleKy,n gp41 K p17, [l pe3Y,llbT3TC ljCfO B03Hl!Kaer H3fll0 ITJJ38M3TIJeJe('KOJ'.i MC'M6pam,I B

171

Mecrax KOHTaKTa llBYX 6eJIKOB, )].JIH TOl'O l'.ff06bl MaKCHMa.ITbHOe Omc.no MO.JTCKYJJ gp41 KOHT3KTHpOB3JIO C BHpycHO}J cep,lI.UeBH­ HOH. Hx B3aHMonei1:cTmre npIrno)lHT K Ta1<of1 cnTyauHrr, KOrAa cqwpH'-IeCK35l cep,ll,uemrna OK33b1BaeTCH f!O,ITHOCTblO OKPYA<eH­ HOH MO.ITCKYJI3MH 6eJ!Ka env. 3aTeM TI0,11, cep,11,1 eBHHOH npOHC­ XO]JJIT CJIJ1Hlll'.le MeM6paHbl, DOJTHOCThIO co6paHH351 BHpycHaH 43CTllUa Tep51eT CBH3b C K.fleTKOH H OCB060}K,UaeTC5l B Me:>KKJTe­ TOl!HOe npoCTp3HCTl30. TTpoTeOJIHTH11CCKOe Hapesam{e npe,lI.­ [IJCCTBeHHHKa ocymecTBJJ51eTCH JIJUllb noc.ne IIOLJ:K0B3HHH mIpyc­ HOH l'.JaCTHUhl, H q:iyHKUHOH3,%HblC 6e.1JKH gag <popMHPYIOT nHyTpeHHHe CTpyKTypbi B BHpHoHe: p24 06pa3yeT KarrcyJIy cep,nuesrr111:,I, a p7 rr p6, acc01urnp0BmnILIc c reHOMHOH PHK, racno.r1ara10TcH BHYTPll Kancy.TJbI, 06ra3y51 cnnpaJTh HYKJ1eo­ Kanc11,a,a. JlHfllb p17 OCT3CTCH CB5l83HHLIM C JTl1DOTTPOTCH,11,HOJ1 060:JO'-lKOfi BHpyca CBOHM Ml!pllCTHJ1HpOB3HHblM N-KOHUOM H npI1 3TOM coxpaHHCT CTa6H,/TbHYIO CB5l3b C TpaHcMeM6paHHblM 6eJJKoM gp41. TT01to6Hoe B3aHMo,a,dicTBHe 6eJTKOB B coCTase BrrpycHOH- 1J3CTHUbl 06bHCHHCT MHOrHe He06bJlJHble .UJIH 060- ,TTOlJClfHblX BttpycoB CBOTTCTBa BH4: Hey.ua,m nprr TIOTTblTKax Bblfl_CJIHTh gp4 l npn pa3pymcm111 13Hpyca 1'lCTepreHT3MH, 06HapyMeHtte gp41 s KOMIT.neKce c p17 n cy6BHpyCHblX lJ3CTH­. uax, Bb!XO.ll. CB06o;uroro p24 H3 BHpyCHblX l'.!aCTHU C noope)K­ JlCHHOH 060.no1rnoii, IJOTepm HCKOBaJieHTHO CB5133HHhlX C gp4l cy6'heJ].HJHIU I!a,D.MeM6paHHOf0 6eJJKa gp120 rr ,up.

J1Hillb rroure rrpoTeOJil!TH'-lecKoro Hapesamrn 6e.nKOB-npe,n­ mecTBCHHllKOB pol H gag BHpycHaH '!3CTHU,a «cospeoaeT» H npHo6peTaeT BmpeKUIIOHHYIO 8KTHBHOCTb.

Heo6L1Hrn1,1fi nyTh 111opcpore1-1e3a RI14 110/l,TBep)KJlaeTcH 3JleKTpOHHO-MHKpOCKOnl!'ICCKHM 11cc.ne,ll,0133HH('M'. y BHOBh o6pa30BaHHblX BHpyCHJ,IX T1aCTHU, OTITO'-IKOBaBlUHXCHOT ITJ133Ma­ Tlfl'.ICCKOH MeM6paHbl KJTeTKH-X03mnia, nech OilTill'.JCCKHTIJIOT·

BHpyCHbIX Tl3CTHU BHJlH3 OTITHlJCCKH Il,10THaH cep.uuemrna. H3MeHO1nnocTh. Heo6bJtH!bIM csoficTBOM B114 HB.nHeTcH BLl­

coKaH CKOpOCTb ero reHCTHl:f('CKO!i ll3MCHHllll30CTH: COCTan 8MH· HOKIIC.TTOTHb!X OCTaTKOB y pa3HhlX H30Jl5ITOB BHpyca OT.TTIIl'.Ja­ C'TCH 60.rJee l'.[('M Ha 20%' CKOpOCTh MyTal(HOHHOro rrpouecca ,ll_OCTiffaeT O,ll,HOH MyTaUHH Ha 104 HYKJICOTll.UOB B umrne pen­

.'IHK3UHH, rrpeBHlU35l B 10 pa3 CKOpOCTb MyTal(HOHHOro npo· uecca y s11pyca rpnnna H B 100 pas - KJJeT01IHOH ,IT.HK. THaO 11onpeMe11110 U opraHH3Me 60.TibHOrO MoryT H3XOJlHTbC51 He­ C'KOJl[,]<0 pa3.r111Om1,rx rrn.uTrmon fHahn B. ct al.. 1986; Von Briczcn HOTct al., 1987; Sakai K. ct THOa1988]. Ce.neKT1mnoe !Ial,0!1,:l('Ill!e pa:rn1iIx napttaHTOB nponcXO)JJlT B KpOB!l ll cnIn1-

172

HOM03fOBOH )Kll,!lR0CTH o;woro H Toro )Ke 60.'lbHOfO. BapHaH­ Thl OT.IIH'la!OTCH ,npyr OT ,npyra He TOJlbK0 ITO HyK.r!e0TH.llHLIM fTOC.TTeJJ.oBaTC.'lbHOCTHM H pecTpHKUHOHHblM KapTaM, HO H 6no­ J]OfH1ICCKHM CBOliCTnaM {Cl<OJ)0CTh perrJHfKamrn, UHTOIT8TH1Je­ Cl{Oe )leHCTBllC). feHeTHlJeCKHe pa::iJJHlJIU! B03HIIKa10T T3K)KC rrpn 3apa>1<emm Honoro xo:i5nma [Goodenow M. et al., 1989], OHi] Jl3I0T ce.TTCKTHBHOC npeIIMYll(CCTno BHpycy, IT03B0.15IIOIIJ,ee rTl)CO)lO.IICTh llMMYHHblC 6apbepu oprarm3Ma. TTo,rr.o6HbIC Me­

<f>CKHHOHHOi-i aHCMIH! JIOUI,u1,cii).

OJU-10BJ)CMCIIH8H ltl!J)I<Y.JHII\IIH IIIT3MM0B C reHCTll'ICCKHMH p33Jllfl!HHMH, npco6Jrn}(8HIIC 0,11,110!'0 11'.l TJIJX 0TpaiK810T HMMYH0· XHM!Jl!CCKIIC II 3 llll,[l,C'MH0.10f1J'ICCI<HC OCO0C'IIHOCTII TTJ)I! B3clHM0·

JlC11CTBHlf BHpyca C opraHH3M0M X0351HHa rsrnith D., Inglis s., 1987; Preston B. et al., 1988; Takeuchi Y. et al., 1988]. ITptt

3T0M Jl3)RC HC3H3ll[-JTeJJhHbl(' MYT3UHH M0ryT rrpHBeCTH K cy­ mecTBCHHblM H3MeHCHHHM 6110.norn11ecKOH 8KTHBH0CTH [Sa­ kai K. et al., 1988]. MeHHCTCSl H Tl)0TTH3M BHpyca. HanpHMep, H3o.nHThl H3 UHC He crroco61-11,1 1rnqrnu11poBaTh T-K.neTOlJHbie

.Jlf!HHH, HO xopomo PD3MJJ0)KaJOTCH B MaKpocparax [Cheng­ Maycr C. ct ::i 1., 19881. B1,u1.e.neHHble OT 60.r1bHhIX H30.nHThI M0ryT 6J,JTI, ptBJ(C.flClll,l rm JlBC rpynnLr B CO0TBeTCTBHH c HX pen.H11Ka1mci'i in vitro: rnpid/high II slow/low. Bnpyc1,1 1-if rpynm,1 xopomo panyT fl ((.JlCT0111-lb!X,ill!HlfHX, HMCIOT 60.nee !llHJ)OKl!ll Kpyr K.nCT0K·X0311C'B, Bbl3hln310T o6pa30B3HHe CHH· HHTHCB. BnpyChl 2-f:i rpymn,! IIJJOX0 J)8CTYT B K.'ICTOlJHh!X .TJH· mrnx H pcJI.r<o 06pa3y10T crrnwrTnir. B11pychl 1-tt rpyrrnbr Bbl·

)RCT 6h1Th CRH33Ha C pa3Ml'IHOii mrpy.'ICHTII0CTb!0 l1IT3MM0B BHpyca, H 0Ha B CB0lO 011epe,llh M0)RCT np!IB0JU'!Tb K HCO,llHHa­ KOBO}I CTeneHI! Bh!pa)KC'HH0CTH KJJHHJPJCCKHX npH3H3ROB npH CTTHU. Pa3Jl!Jtnrn MC)RJlY UITaMMaMn, 06pa3y1orn.HMH H He 06pa3y1omHMH CHH[(HTH!1, o6nHCH51lOTC51 p51,IJ,OM TTJ)HlJHH: 33MeH01I 3MHHOKHC.'I0THblX 0CT3TK0B B C00TBCTCTBY!Olll.HX yLJaCTKaX MO· JTeKyJ1b1, MO,IJ,mjJHKaUHRMH B npouecce rJTHJ<03HJJJTJ)OBaHHH, KO· TOpoe f!B.!JHCTCH cymecTBCHHblM cpaKTOPOM IIPll (pOJ)MHp0BaHHH CHHUHTJrn. JT3MeHeHH5!MJJ B cocTane LTR, 06ycJJOBJJHna1011u1MH pa3.Jl[l'IH· YI0 lJYBCTBIITe.'lhH0CTh K KJJeT0llJ-IbJM aKTHBaTopaM TpaHc1<p11nrum, He)].oCTaT01moii 3KTTIBHOCThIO reHa tat, Heo6XOJI.HM0CThl0 IJC!l0Jlh30B8Th ;xpyroi'i ]{JICT011HhlH peI CITT0p H ,ll,p. 31rn1rnTe.;1hHy10 poJIT, Fl TT05113.!!ClIHII H0BhIX BapmrnT0B MoryT

173

HrpaTb roMoJJonP1ecKHe peKoM61rnauH11 [Srinivasan A. et al.,

HcycHC0I

no Mepc rrporpecrnpoaatt1rn 60J1e3He11 BhIAeJrn10Tc5! BHpy­

lOTC5! no reHy vif, onpe,neJJ5!I0W.eMy HH<f}CKUHOHHYIO aKTHB­ H0CTb BHpycm,1x qacrnu [Fenyo cTOet al., MObBKoaOBepoHTHo,

B opraHH3Me 60.!JbHblX rrpoHCX0AflT CCJICKUIHI BhIC0K0naroreH­ HblX BapH3HT0B B npouecce a,ll.arrrar.urn K X03f!HHY H HX ycH­

JlCHHafl penmIKau1rn B yc.r10B1rnx HMMyH0Aeqn1u11Ta [Boylsto­

ne A., Francis OIeTIoIcyylpI

AHTHreHHble CBOHCTBa. OcHOBHblMH npoTeKTHBHblMH aHTH­ reHaMfl BI,fLI, KaK H y APYrHX 060J1011e'lHbIX Bupyccrn, HBJJH10Tc5! rJll1K0npoTeH,Qbl gp HyC3 gp4 Cp3

MIC0CTaBe 6e.TJKOB env B114 c II0M0W.bIO K0MilblOTepHoro

aHaJJH3a o6tiapy}KCHbl HHaaHTHremiblX ,neTepMHHaHT, 9 H3 KO­ TOPb!X .10KamnyIOTC5l B gp nIyC311 KIB 6CbIl. OCHOBHblC )l,CTep­

MHHaHTbl B C0CTane gp BcCT3K0T0J)b!MH B33HMO,UeilcTByIOT BHpycHeihpaml3yIOnu1e 3HTHTCJ!3, HaX0)l.5!TC5! B ABYX 06JJ3C'f5!X Mo.neKyJJhI. OcHOBHOH ciITHTon, K0T0pbIH y3naeTcH B11pycneii­ TpaJJH3y1011u1MH aHTHTCJ!3MH, pacnoJIO.lKeH MC:iKAY 0CTaTK.aMH MCK3H oOK3B M0M3Bapua6eJibHOfI o6JJ3CTH M0JICKYJlh! 6e.rma. Ott npe,uCTanJJHeT co6oif neTJJeo6pa3Hy10 cTpyKTypy, co 'l.ep)Ka­

w_yta 24 aMHH0KHCJ!0THb!X 0CT3TKa. I30CH0BaHH5! neTJJH Haxo­ ,ll5!TC5! ,usa UHCTCHH0BblX 0CTaTKa anCye5!b3II ppCT0eaHHCB5!3aHHhIX

,n11cyJ1bq>HAHbIMH CB5!35lMH. O6a 0CT8TK8 BbIC0K0K0HCepBa­ THBHhl. OcI-IOBHOli 3DHT0il HaX0,ll.HTC5! Ha seprmrne neTJIH, OH C0CT0HT l!3 8 0CT3TK0B H C0ACp:iKHT K0HcepsanIBHble Il0CJJe­ J].0BaTeJibH0CTH fJIH - llpo - LTJ!I. 3TOT 3TTHT0fl 0Kpy:iKeH

rnnepBapbHpyIOJHHMH 0CT3TKaMH, pa3JIH'i3lOJH!IMHC5! 1/ pa3Hb!X H30JIHT0B l6H3 [Skinner M. et al., pbBByOJavaherian I(. et al., pbBbnO(ex. c. CHHH0OAnTHTeJia npoTHB ciToro yqacTl(a nef-iTpa­

JIH3YIOT llllcpeKLI,HOHHOCTh BHpyca H TI0)l.clBJl5!IQT CJJHffHHe 3apa­ ):l{CHHblX KJJeT0K, 0,UHaR0 0HH He 6JJOKHPYIOT CB5!3blBaI-1He C I\JlCTQlJHbIM peue1nopoM. EcTeCTBeHHO, 3Ta HMMYH0A0MHH3HT­ Ha5! o6naCTb ,11.0Jl)KJla 6b1Tb npe,ll.cTaBJ1e1rn B B3KUHHe np0THB CnHn, 110 cepbC3HblM npen5!TCTBHeM K 3T0MY 5!BJ151CTC5l rn­ nepnap,rn6e.'lbHOCTb 0CTaTK0B, <l)JiaHKHpymmux ue1npaJ1bHhll'-i y4aCT0K. B 6y.uyw.eM B03MO.lKH0 npe0)I.0JICHHe 3T0r0 npell5!T­ CTBH5! nyTCM HCII0Jlb30BaHH5l CMCCII nenn1.non 113 3TOH o6JJa­ CTH, C00TBeTCTBYIOillJIX pa3Hb!M napnaHT3M B114, JJH60 rn6p11,UHbIX nenTlf,ll0B.

D,pyrnM 3llHT0fJ0M, C K0T0pbIM B3aHMO,llC1ICTBYlOT Bllpyc­ HCHTpa.11113yIOIJUIC aHT!!TeJia, 5!BJJ5!CTCH KOHCepnaTHBHblH ytia-

HTa0

370

TM

395

CxeMa 4. CTpyKTypa KJICTO•rnoro pcuenTOpa CD4.

C"!'OK: C - [\IITOHJla3MUTll'!eCKllJ1 y,1acTOK, apa6CKHe l\I!<Jipbl -nop<1,n;KOBhle aMIU!O· KllCJ!OTllblC OCT3TKH.

CT0K gpl20, y31-ia10mni1 peucrnop [Goudsmith J. et al., I988J. O}].HaKO B opraHH3Me HMMYHH31!p0BaHJ-Ib!X )KHB0THhIX aHTHTe­ JJa nponrn 3THX y'!aCTK0B gp 120 He II0HBJl5110TC5! B CB5!3H m-r6o C }].eHaTypau11ei1 3IIHT0il0B, JJH6o C HX HH3KOH HMMYH0reH­ HOCTblO [Skinner M. et al., 1988]. Heco rneHHO, BaKUHHa npo­ THB CrII1,ll, JVIH Toro 1no6b1 HHAyuupoBaTb npoTeKTHBHbI11 HMMYHHTeT, ,Lf,0JOKHa C0,Ll,ep:i!<aTh o6a 3IlHT0Tia. ECTb H )l.pyrne 3IlHT0ilbl, Y43CTBYI0l.l(HC B HettTp3JIH33UHH, 0Jl,H3K0 0HH MaCKH­ p0B3Hbl Ha ll0BCpXH0CTH 6eJlKOB env H Bb!HBJIHIOTC5I JIHlllb B CHHTeTIP1eCKHX llCTITH,ll.ax. MaCKHpOBKa aHTIIrCHHbIX ,11,eTCpMH· HaHT, J333HMO,Ll,ei'icTBYIOllLHX C BHpycHeihpamrnylOJJlHMH 3HTI1· TeJiaMH, 5!BM!CTCfl OCHOBHOH IIf)HllHHOll 0TCYTCTBIU! np0TCKTHB·

H0ro 3q>cpeKTa aHTHTeJI, 06pa3y10U.l,11XCfl y JII0,11,efr, HHqJHUHp0BaHHblX Blll.J.

B npoTHBonoJio)!{H0CTb gp I20 gp4 I He co,11,epJKHT urnpoKo napbHpyI0Ul,HX y'!aCTK0B. MeJK)ly rH,L1,potjJo6tthlMH rpynnaMH HaX0,ll.HTC5! rJIHK0311JIHp0BaHHbll1 y'!aCT0K (3ITHTOH X)' o6Jia­ )13IOULHH Bblpa)!{eHJiblMH aHT11re1rnblMH CBOllCTBaMH. OH M0JKeT 6b!Tb 3KCCT0HHpoBaH Ha nonepxH0CTH 1rnpycHOH '18CTHI(bl 11 Y3H3B3TbC5! <paKTOpaMH HMMYHHOH CHCTeMbl opraHH3Ma. 9THM 06bHCH5IeTC51 H3Jilfl!He 3H3'1IITe.nbl10ro K0J!l1'1CCTB3 aHTHT,;;.'J

17:

nponm .9T0f0 6eJIKa B opraHII3Me 3apa)!{eHHbIX JIIIIJ:. ,UaHHblll ytJaCT0K 0TJIII1IaeTC5I He3Ha<rnTeJibHOH BapHa6eJibHOCTblO 11, II0-13H)UIM0My, 13L!TI0JIH5ICT 6ttOJIOf!Jl!CCKH 13a)!{I1Lle qJyHKU:1111. I1MCl!HO C !!IIM M0)!{CT 6LITb CB5I3al!a qJy!IKU:115! CJlll5Ill115I C KJie­ T011HOII MCM6pa!IOH npH 11p0HHKH0l3emrn 1311pyca 13 KJICTKy. 3n11TOI! XI C0,l!,Cp)!{HT 0CTaTKlf r11.n:.pocjmJILlfLIX aMHH0KlfCJIOT H npe,LI.CTaBJIHCT co6oH, Bepo5ITH0, 5IK0p11b!C II0CJie,LI.oBaTeJib­ H0CTll, npHJieraIOI.IJ,I1e eT TpaHCMeM6paHIIOH o6JiaCTlf.

KJieTO'IHhltt pel.\enTop H 11yacTBHTeJibHOCTh KJieTOK K Blf ll.

Cpc.n:.11 LJYBCTBIITeJibHb!X K BIIpycy KJieTOK Ha nepB0M MeCTe 1-1axo,LI.5ITC5I T4-JIHMqJOU:lfTbl, K K0T0pb!M 0TH0CHTCH T-xeJinepu n T-111-1,LI.yKTOpb!. B11pyc M0)KeT 3apa)KaTb 11 .n:.pyrne KJieTK11: MaKpocpar11, M0H0IJ:HTbl, HeK0T0pLie KJI0l-!bl B-KJieTOK, KJieTKH Jianreprar1ca, XOT5I IImjJeKU:115! .9THX KJieT0K He Bcer,l!,a conpo130)!{,LI.aeTCH o6pa3oBaHJ1CM IIHcpeKU:HOHHoro I!0T0MCTl 3a H IIMe­ CT a6opnIBIILIH xapaKTep. MaKpoqJarn H M0H0U:IITbl HMeIOT cy­ IlLCCTBeHIIOC 3HaLJeHlfe 13 naroreHe3C m1qJeKU:Hlf, yqacTBY5I 13 ec reHepaJIH3aU:HH H npoHHKH0Bemrn BHpyca aTUHC (BHpyc­ HbIC aHT!ffCl-!bl 061-1apy)!{ ll3aJOTC5I aTKJieTKax M03ra, acTp0U:H­ TaX, HeHpOrJIHH); .9TH KJieTKH o6LI'IHO He norn6a10T IIpH 3apa­ )!{eHlfH BlipycoM H cnoco6cTByIOT cpopM11po13aHIIIO nepCHCTeHT­ !ILIX qJOpM lIHqJCKU:Hlf.

l.JyBCTBHTeJILHOCTb KJieT0K K BI14 o6yCJIOBJieHa HaJilf'-!HCM 1-1a 11x no13epxH0CTH cneu:HcpH'-!ecKoro peu:ernopa CD4, 11pe,LI.­ craBJie1-rnoro 6eJIKOBb!Mlf M0JieKyJIaMl!, C K0T0pb!MH B3aHM0- ,l!,eHcTByeT 13HpycHbIH rmmonpOTeH.n:. gpl20. HaH6oJiee BbIC0Ka5I IIJiornocTb peu:enTopa CD4 Ha noBepxH0CTH T4-JI11Mcpou:H­ T0B o6ycJIOBJIHBaeT, II0-BH,LI.IIM0MY' HX Bb!C0KYI0 11yBCTBl1TeJIL­ H0CTb K BHpycy, 6oJiee Hlf3Ka5I IIJIOTH0CTb 061-1apy)Kel-!a 1-1a II0BCpXH0CTH MaKpocparoB II ,l!,pyrnx nepe1rncJieHHb!X KJieT0K.

PoJib MeM6pa1-1Horo rJIIIKonpoTe11.n:.a CD4 aT npou:ecce BI1l.J-HHcpeKU:HH 6wrn yCTaH0BJieHa pa3Hb!MII nyrnMII: 6JIOKH­ poBa1-111eM BI1l.J-H1-1cpeKU:lfH aHTII-CD4-aHTHTeJiaMII, npII06peTe- 1-111eM qyBCTBlfTeJibH0CTH K IIHqJCKU:HH KJieTKaMII CD4 np11 TpaHcqJcKu:1rn reHa CD4 [Bedinger P. et al., T0HHcano6pa30Ba­

HIICM CTa6HJibHbIX K0MIIJieKC0B CD4 c gpl20 [Lasky L. ct al., THHKonCJM6OnD. et al., p0HKcenMoJieKyJIHpHaH Macca CD4 0K0·

JIO 55 000, aTero C0CTaBe IIMeIOTC5I yqacTKH J'OM0JI0fHlf c 6eJI­ KaM!f cynepceMeHcTBa HMMYHOrJio6ymrnoB. EeJioK IIMeeT 4 Ha,l!,MeM6pamrne HMMyHorno6yJrn1-1rro,LI.06HL1c o6Jiacrn VI­ V4, o,2L1-1y TpaHcMeM6paHHYIO o6JiaCTb II U:HTOI!Jia3MaTH'-!ecKHH XB0CT 113 40 aMIIH0KHCJI0THb!X OCTaTK0B (cxeMa 4). OcHOBIIOH ¢y1-1KILHett CD4-MoJieKyJI, uaxo,l!,HLIJ:11Xc5I 1-1a noBepxH0CTH T4-JIHMqJOU:HTOB, 5IBJI5IeTOI Y3HaBaHlfe aHTHreHa aTK0MIIJieKce c 6eJ1KaM11 KJiacca IBnpTeaKHaxo,l!,5ILIJ:HMHC5I na noBepxHocrn

176

1988; Jameson B. et al., 1989]. ,[le-

TepM11HaHTb1, Tpe6yIOI.IJ.HeCH ,ll,JIH cpyHKI..1,llOHaJibHOH aKTllBHOCTH CD4, pacrroJ1ara10TCH BO MH02KCCTBeHHblX yqacTKax rrepBb!X ,ll,nyx o6JiacTcii Vl H V2 [Lamarre D. et al., 1989]. O,ll,HaKo HCCMOTpH Ha pa3Hb!C yiraCTKH CBH3b!B3llllH MOJICKYJI, gp120

.9cjJcjJCKTIIBHO HIII'II6HpyeT OCHOBHYIO cpyHKI..l,lllO T-KJICTOK - BOC­ np1rnn1e Clll'IIaJIOB OT aIITIIJ'Cimpe3el-lTHPYIOI.IJ.HXJlllMqJOI..1,HTOB, 6JIOKHPYH CBHJLmamre 6cJ1KoB KJiacca II. Bo3M02KHO CTepH'-Ie­ CKOe ,ll,eHCTBHe gp I 20 1-13 3TH ytJaCTKll JIH6o H3MCHeHHe MOJie­ KYJibI CD4 rro,ll, B03,ll,eiicTBHeM gp120.

B3aHMO,ll,eHcTBHC gpl20 c CD4 xapaKTepH3YCTCH BbICOKoii acjJqJHHHOCTblO. B CBH3b!B3Hlle C pe1..1,eIITOpOM BOBJielfeHa yrne­ BO,ll,HaH '-JaCTL MOJieKyJib] gp120 [Pal R. ct al., 1989], oco6oe 3Ha'-IeHHe HMeIOT OCT3TKll M3IIH03LI, CBH3b!BaIOI.IJ.llH M3HH03Y KOHKaBaJIHH A 3cpcjJeKTHBHO lIO,ll,aBJIHCT B3aHMO,ll,CHCTBHe C pe- 1..1,CIITOpOM [K.azazi F. ct al., 1989]. ,[lpyrne aBTOpbl IIOJiaraIOT, '-ITO rJIHK03llJIHponaHHC !IC BJIHHCT Ha CBH3bII3aHHC gp120 C pe1..1,eIITopoM [Cordonnierc A. ct al., 1989].

Y3HananHe MOJICKYJIOH gpl20 MaJieHbKOH rreTJIH Ha MOJie­ KyJie CD4 ocymecTBJIHeTcH rryTeM B3aHMO,ll,eiicTBHH c .9TOH rreT­ Jieii aMHI-!OKHCJIOTHLIX OCTaTKOB, pacIIOJIO)KCHHblX Ha ,ll,He yrny6J1e1-1m1 (HJIH K3pMaHa) Ha noaepxHOCTll MOJICKYJ!bl. Tio-BH,ll,HMOMY, HMCeT MCCTO Ta Me CHTya1..1,HH, KOTopaH 6blJia Ol1l1Ca1-1a ,ll,JIH BHpycon rp11rrrra H pHHOBHpycoB: y HllX Y3HaIO­ I.IJ.HC pe1..1,errrnp IIOCJie,ll,OB3TCJ!bHOCTH I-13XO,ll,HTCH Ha ,ll,He Kap­ Mana (HJIII K3HbOIIa)-y3KOll I.IJ.CJIH, o6eCIIC'-Illl33IOI.IJ.CH33I.IJ.HTY OT 31-!TllTCJI (CM. rJiaBy 4). TaKaH JIOK3JI!l331..1,llH II03BOJIHCT rrpe,LI,OTBpamaTb J(CHCTBHC ryMopaJibllOro HMMYHHoro OTBCTa

1-ia caMb111 paHHHH 9Tan BHpycHOH HHcpeKLUHI - a,11.cop6umo BH­ pycttwx yaCTHU Ha KneToqao!'i noBepXH0CTH. YqacTOK y3HaBa­ HHH peuell'ropa BhlC0KOK0HcepBaT1rneu, ITOCK0JibKY 0,11.HH H TOT iI<e pe1lenrnp Y3HaIOT rJJHKonpoTe11,11.b1 BH4-l, BH4-2 11 BHO. 9ToT Ko11cepsaTHBHh111 ya1acTOK cny)KHT xopornett MH­ llieHbIO ,11..rrn ,11,e1krn11H aHTHB11pycttbIX npenapaToB. C ,11.pyroii CTOp0Hbl, 60.TJeenpOCTblM ITO,ll.X0,11.0M HBnHeTCH HCITOnb30BaHHe attaJroron CD4, KoHKyp11py1011lHX c npHpo,11,HhIM peuernop0M 3a CBH3b!B3HHC C gpl20. TaKHM npenapaTOM cnyiKIIT paCTB0pH­ Ml,IJ1 6enoK CD4 (pCD4), CBOHCTBa Kornporo II ne•1e6HbIH 9cp­ cpeKT on11ca111,1 B mane 12. Bo.nbllIHM npe11MymecTBOM pCD4 nepc;( 11.pyrHMI-r npcnapaTaMH HB.TTHIOTCH OTCYTCTBJJe K0HKypeH- 1.1.HH 3a CBH3LIB3HHe np11po,11,1rnro CD4 c 6eJ1KaM11 Knacca II MlIC H coxpaHeHHe cpyHKUHOH3JibHOi'i aKTHBHOCTH T4-JJHMcpo­ UHT0B [Lamarre D. et al., 1989]. DpH 9TOM npenapaT 9cp­ cpe1nHBeH npH 3apaiKeHHH K.TTCTOK pa3Hb!MH H30JIHTaMH B114-1. ,U.nH BH4-2 Tpe6yIOTCH 6onee BbIC0KIIe K0HUeHTpaUIIH pCD4 JJH60 13 CBH3H C 60JJblllCH TIJI0TH0CTblO M0JJeKy.n gp120 Ha TIOBCj)XII0CTH BH4-2, JIH60 H3-3a HH3KOH acpcpllHHOCTH gp120 BH4-2 K CD4 [Byrn HeHet al., 1989].

3apa.iKeHJ:reBH4 CD4+-.n11Mtj)OUHTOB 11pHno,11.1-n K 6blcrpo­ My yMeHblllCHHIO HJfH ,11.aiKe HC4C3H0BeHHIO M0JJeKyJJ CD4 C K.TTeT04HOI°I II0BepXH0CTH, 11 9T0T npH3UaK HBnHeTCH Ha,11.eiKHbIM MapKepoM nporpccCHpoBaH1rn BH4-HHtj)CKUHH. DoTepH peuen­ Topa CD4 M0)KeT o6bHCHHTbCH pa3Hb]MH 1IpH4HHaMH: yMeHb­ WCHHeM KOJ1w1ecTsa MPHK ,11..nH CD4, H3MeHeHHeM csorkTB Mo.neKy.TJ CD4 11 HX HCOTI03HanacMOCTblO, HaKOHeu, o6pa3oBa­ HHCM K0MTIJICKC3 CD4 C nupycHhfM 6eJJKOM gp160 B UHT0TIJJ33-

ra J. ct al., 1989]. B KaKOH-TO CTCTICHH 9T0 M0iKeT 6b!Tb CBH3aH0 C ,11.eCTpyKuHeH 3apai[{eHHblX KJJeT0K II ceJJeKUHCH CD4--KJ1eTOK.

CBH3Lma,me gpl20 c peuemopoM CD4 HMeeT eme 0,11.HH acneKT, HervraJJoBa)KHbIH ,11.JIH naToreHe3a HHtj)eKUHH. CB060k Hblll gp120, OTJJOMHBWHHCH OT TI0BepxH0CTH BIIj)H0Ha H.TTH 3a­ j)3)1{CHHOH KJJCTKII, CBH3UBaeTCH c MoJJeKynaMH CD4 Ha no­ BepxHOCTH HOpManbHblX T-KJJeTOK H CBH3LJBaeT cneuttcpHYeCKHe aHTHTCJJa, UH])KY.TTllJ)YIOLQHe B CbIB0pOTKC Kp0BH 3apaiKeHHbIX JJHU. O6pa3y101QHHCH Tj)HMo.1eKyJ1Hj)HblH K0MTIJJCKC 110,11.aB.TTHeT aKTHBaumo T-KJieTOK ,11,aiKe npll HH3KHX KOHUeHTpauHHX 060HX K0MTI0HeHTOB [Mittler HKaHHoffman M., 1989]. TaKHM o6pa30M, BH4-cneu11cj)HqecK11e aHTHTena B3a11Mo,11.el'icTBy10-r c peuenropoM CD4 nprr nocpe,11.crne gp120 11 KaK 11 T11nrrqtt1,re aurn-CD4-aHT11TeJia 6JI0K11py10T cpyHKUHIO T-KJJeTOK. B opra-

aeKH

HH3Me 6oJJbHbIX CITI1,U II IIHqJHI.])1pOBaHHhIX B1,1pa6aTbJBaIOTCH aHTHTeJJa npoTHB CD4, o,IJ,HaKo 11x poJJb n naTore11c3e CITMJJ. He ycTaHOBJJCHa [Kowalski M. ct al., 1989].

,UaJJeKo He Bee CD4+-KJJeTKII MoryT 6bITb 3apmKeHb1 BH·

lJTO MO)l(eT cymeCTBOBaTh KOpe,i:cnTop Irn!I ,IJ,a)KC ,Il,pyroH pe­ uenTop ,IJ,JJH Bl14. Bo-nepBbIX, He nee T4+-KJJeTKII MO)l(H0 3a­ pa3HTb BIIPYCOM B 9KCncp1IMe1nc: IIIIqJeKIUrn B03HlIKaJJa Jllllllb 13 10 20% KJJeTOK. Bo-BTop1,1x, nBCJJ:CHHe reI-Ia CD4 (TpaHc­ cpeKUIIH) B KJJeTKn, He co/i:cp)K,11u11c cro (KJJeTKH HcLa, MbI­ m1rnb1e rjrn6po6JiaCThl, rII0JHl}lhl 1IC'.TJORC11CCKHX II MbllUHHblX T-JJ!IMqJOUHTOB), X0Tb H 06ecne111rnaeT npIIKpenJJeHHe nnpyca K KJJCTKaM, O}Ul3KO HC BCer,IJ,a nprIBO,Il,lIT K p33MHO)l(eHmo BH­ pyca. ITo-BII,IJ,IIMOMY, neo6xo,IJ,IIM erue K3KOII-TO KOMTI0HeHT KJJeT01IHOH TIOBCpXHOCTII, 1IT06LI np1IKpemrnm111'ic51 K peuenTopy BHpyc Mor npOHIIKHYTb B KJJeTKy.

Oco61,1i'i mnepec BbI3LJBaeT 11yBCTBHTem,HOCTb K B114 KJJe­ TOK M03ra. ITopa)l(eHIIH M03ra pa3JJ1111Hoi'i CTcneHH, OT Hapy­ rnemrn TI3M51TH }i:0 rny6oKlJX }i:IICqJyHKUHli, MOTOpI-IblX Hapyrne­ HIIH II rny6oKOH ,Il,CMCHlUIII, xapaKTCpHLI JLJJH IlHqJCKJlH!I B114. B cepoM II 0C.TTOM BC'IllC'CTRC o6napy)l(CHLI nnpycHblC aHTlffCHbl H npon11pycHI,IC TI0CJIC}lOB,lTC.TThll0CTII. MoIIOillITLI H MaKpocpa­ rH B JJ06Hor'i,13HC01JJIOH H TCMCHHofi ,Il,0J151X C0}lCp)lrnT aHT!IfCHhI B114. C TI0M0IUbIO MOJJCKYJJHpHoi'i rn6pIIJi:II3aUIIH npoBnpyc o6Hapy)l(eH B KJJeTKaX 9H,Il,OTemrn KaTIJIJJJ151pOB M03ra, n,­ raHTCKHX KJJeTK3X, M0H0UIITax, MaKpocparax, aCTpounTax. B ncpeBHBaeMbIX JJIIIIllHX KJJeTOK M03ra npoHCXO,Il,IIT pcrnm­ KaunH B114, XOTH II B 3Ha1nITe.1bH0 MC'llbUiei'i CTcneHH, IIeM B T4-JJnMcpounTax [Srinivasan A. ct al., 1988].

O,n:HaKo Ha noBepxnocTH KJJeTOJ< KYJJbTYP, noJ1y11eHHbIX H3 3J10Ka11ecTBeHHb1x onyxoJJerr M03ra, He 61,u-10 o6napy)l(eHo pe­ uenTopa CD4, xoT51 He3na1rnTeJJbI-Ioe KoJJn11ecTBO MPHK ,IJ,JJH CD4 n 6b1JJ0 Bbl51BJJCHO. Anni-CD4-aHTIITeJJa He 6JJoKnpoBaJrn HH<peKUHIO. B TO )l{e npeMH KJJeTKII 6bIJJIJ lJYBCTBHTeJJbHbl K B114-1 II BHY:-2 [Weber J. et al., 1989; Clapham P. et al., 1989; Harouse J. et al., 1989]. ,UaJree, MaKpoqJarn Ha 5-e cyr­ KH TIOCJJe npnKpenJJeHHH K TIJJaCTHKY TIOJllIOCTbIO yTpaIIHBaJJH CD4, 0,IJ,HaKo coxpaH51JJII 11yBCTBIITeJ1bHOCTb K BHpycy [Kaza­ zi F. et al., 1989]. B114-2 cnoco6eH 3apa311Tb JJIIlllb onpe,IJ,e­ JJeHHbie JJIIHIIH CD4-KJJeTOK, CJJe,IJ,0BaTC.TlbHO, ,Il,JJH a,IJ,cop6urrrr BHpyca Tpe6(rn;im1cb Ji:pyrne M0JieI<ym,1 (noM11Mo CD4) [Ho­ xie J. ct al., 19881. HaKoHen, Bl1l.-J-IImjJcKIU151 B03HHKa.na np11 HCTT0Jib30B3JUIII CD4 C y,IJ,aJJCIIIILIM Y1IclCTK0M Cl3513I,JBaHirn C

12*

gpl20 lMaddon P. et al., 1988]. Bee 9TH ,ll.aHHbie cBHAeTeJih­ cTBYIOT O H3JIIJT11H! clJlbTepHanrnHoro penerITOpa HJ!H Kope­ uemopa.

IlpoHMKHOBenue B KJieTKY M cmunrne MeM6paH. KaK JI mo6aH BHpycttaH IHH!)CKUHH, CITM,ll Ha HaIJaJJhHOH CTaJJ:mI KOHTpOJIHpyeTCH no Kpai'rnei'IMepe ABYMH HC3/l13HCHMblMH MC­ X3HH3M/lMJI. I. Tiprmpell.iICHHC K KJieTOlJJ!()H Il()I3epxHOCTH, o6yc­ JIOBJICHHOC 83/lHMO/lCHCTBHCM npHKpenHTeJibHOfO 6enKa BHpy­ ca co crreumjJil'ICCKIJMH peucn-ropaMH. 2. TIpoHHKHOBCHHC B KJICTKY nyTCM CJ!IUIHHH BHJ)YCHOl1 o6om)!JKH c KJICT0T1l!Oi'I MeM6pa110H, o6ycJJOBJiemwe B3aIIMO!leikTBrreM wroporo noBepx11ocTnoro 6e:JKa, 6eJIK3 CJU!HHHH, C Jllll1ll)J,3MH KJICTCFIHhlX MeM6paH. B pe3yJibT[1TC imyTpeHHHII KO\rnOHCHT BHpyca npo­ mmaeT B KJICTKY H TJ)3HCIIOpT11pyeTCH K onpe,ll.eJICHHblM KJ1C'· T011Hb!M CTPYKTypaM, rJIC OIi BU3blB3eT HHlj)CKIUIOHHhlH IIpo­ uecc.

ITp1mpc111nc.111,n1,1M 6CJIKOM BHLI r1BJJHCTCH gpl20, 6eJIKOM cmrnHHH TJ)3HCMCM6pam11,1i'1 6e.rrOK gp41. DCJIOK gpl20 - 11a1160Jiee Bapna6eJTI,Hhiit 1rnpyc111,1il Gc.noK, OJJ.HaKo yTrncTOK, B3aHMOJJ:eiicTByrouurit c pcncHTO()OM CD4. 06Jia;1_acT B1>1c0Koil. KOHCCf)B8THB!IOCThlO H fOMOJIOril'lE'H B COCT3BC BI14-l, BHlJ-2 H BHO. 3TOT yTiacTOK HaxoJJ:HTCH y C-Kcmua Mo:1cKyJI1,1 B 06JiacTn 3MHHOKHCJ10THhIX OCTaTKOB 406 417 HJIH 468-511. Ha CBH3brna1rne gp120 c ·pcuerrropoM CD4 BJ11rn10T II B1>1coKo­ KoncepBanrn1me o6JiaCT!I B UCHTp3JihlIOll H N-KOHUCBOl1 qacTH MOJieKyJiu; 9T3 3aeHCHMOCTb o6ycJIOBJICHa yqacTHCM )J,3HH X o6JiaCTCJI B KOH(j)OpMaIIHOHHblX 9(pq)CKTaX, B03IIIJKaIOIIUJX 33 C'ICT )IJ!CYJib(j)l!T(HbIX Cl3H3et1 M!:.'2KlIY pa3llb!MII T1acTHMH MOJIC·

TeJibHOCTHMH HA2 6eJIKa B11pyca rpmrna H oco6euno F-6cJ1Ka napaMHKCOBHpycoB. 6eJJOK-11pCT(Il1CC'rBeHIIllK env gpl60 Ha­ pe3aCTCH TOHagp120 II gp41 B yHrncTKC J1113 -Apr. lh!}Ke 9TO· ro Y'IaCTK3 H3XO,[(HTCH 7 OCTaTKOB rH,ll,pocpo6Hb!X KOHcepBa­ THBHbfX aMIIHOKHCJIOT, 6 H3 KOTOpb!X npeJJ.CT3BJ!5IIOT co60H nHIJLCM 3 OCTclTKOB, 0611apy1KCHHblX ll B 6e.1rnax C,JlJUIIIIJH BH· pycoB rpurma H rrapaMIIKCOBHpyccm ©eH - J1ei"I - fm1. B 9TOH

BI1ll-2 H BHO STLV-3, XOTH oCTa,TibHbre y11acTKH noro 6eJIKa IlIHJ)OKO B3f)bHJ1YIOT B C'OCT,me 3TIIX 1rnpycoB If J(<l)!{C l!X pa3llb!X H30JIHTOB. YKa3aHilaH KOHcepB3T!IBII3H o6JJa('Th t1pe3Bbl­ IJ8HHO cxomw c amworwwuM yT1acTIWM F1 -6emmn napaMI!K-

180