BaropoM. Ycnex rro,L1.00Horr cTpaternn HJIJIIOcTpIIpyeTCH B03· HIIKH0BeHJieM YCTOI°PIHBOCTH K.f!CTKH K BI1r npH BBe,neirnH B KJICTKY re1rn, K0,Ll.IIpy1omero cpparMeHT TpancaKTHB3Topa VP16. fieJIOK 3KTIIBHpyeT CBCpxpamrne re!-Ibl, a e0paHCI10Jlb3YCMblH cpparMCHT B33HMO)].eficrnycT C KJJCT01 !Hb!MH 6eJIK3MlI, CBH3bl· uaIOill.IIMIICH c KJieT011110H ,l.UII< H 06ecneIJnnaIOI1.UIMII TpaHC· 3KTIIB3IJJ!IO. B pe3yJibT3Te KOirnypeH!.lHII 6JJOKHpyeTCH Tpauc Kp!U111,HH CBepxpaHHHX reH0B BHpyca. Ta }Ke CTpaTerHH MOlKCT 6b!Tb np11MeHeI1a J].JIH 33Ill.HTbl OT JJ.pyrnx BHPYCHbIX lIHCpeK•
11,IIH, npH K0T0phlX ycTaH0BJICH MCX3HlI3M )].eiicTBHH TpaHC· 3KTirnaT0p0B (cM. rmrny BTeyBaltimore H0MaaTyH33B3Jl TaKy10
cTpaTermo 33ll(IlTbl KJICTKII OT BHpyca BHYTPHKJICT0HmoH HMMY· Hl!3311,HCll. EJUl3KOC naupaBJICHl!e CTpaTerrrn XllMH0TepanHH 33KJII01IaeTCH B IICIIOJ!b30B3HHH TpaHC,l(CHCTBYIOIJJ,HX npoJJ.yKT0B KJieT0lJHblX reH0B, o6ycJJOBJIHB310IlJ.l!X pe3HCTCHTH0CTb KJICT0K
K )].aHH0MY Bnpycy. I10JJ.06Hble KJieT0'IIlbie reHhl 06uapy2KeHbl no ornomemno K BHpycy Hmypa [Torre BHaet al., 0MKMopy
PenJIH K a I H H B H p y c11o r o reH o M a. Ee BapnaHTbI CT0.'lb )KC MHOr0tillCJICHIIbl, KaK 11 TpaHCKpIImurn; 3H3lJHTCJlb H3H HX tI3CTb M0,KeT CT3Tb o6oCKTOM XHMH0Tepamm.
HTco,KaJ1enHIO, ecJrn He ctrnTaTb y)Ke yn0M5IHYTbIX cmne30B y peTposnpycoB, npoTCK3!0IlJ.HX C yqacTHCM peBepTa3, 0611a,ne1K1rnaiom11e pe3ym,TaTb1 noKa He noJ1y11eHbI. CpeJI.H ny Tci"1 B03)(eiicrn1rn 11a TpancKpHTIIJ,HIO H penJIHK311,H!0 CJie,nyeT TaKlKC o603Ha'lllTh eme 0) HH TIO.LI.XO)]. - CIIHTe3 If .[I,OCT3BKY B KJlCTKH IIOC.1C)].OB3TCJlbHOCTeH, K0MTIJieMCHTapHblX BHpH0H· HhIM HYKJieHH0BbIM KHCJIOT3M HJIH BHpyccnel.llHfJH'lCCKHM HYK· JICHH0BbIM Kl!CJI0TaM, o6pa3yIOill.HMC5I B xo,11-e penp0,1lYKIU!H
BHpycos. By,nyirn K0MI1J1CMCHTapHblMH H cpaBHHTC;lhH0 ae6oJlb· HIHMH 110 paaMcpaM HpeT0eaHYKJICOT!IAOB), 0HH M0ryT H3HTH
HCK0My10 CTPYKTYPY· EcJIH 2Ke nx «cna6,nHTb» aJ1KHJ1Hpy10mH· Ml! HJIH JJ.pyrnMH COCJ].HHCHHHMH, IT0BpC1K)].3IOJJJ,HMH MaTpHil,bl, TO 0HH MoryT CTclTb CB0eo6pa3Hb!M cpe.ncTB0M HCTpa,nHIJ,H0H· uoii XHMH0Tepamm rrnpyc11b1x nmpeKUHH. Bo3M01KHO TaK2Ke IICl10Jlb30B3HHC JIHII0C0M / JI5I BBe,nemrn 3TIIX 0J1Iff0HYKJIC0TH Jl.0B B KJICTKH Il 33Ill.HTbl HX OT ,nerpa,naIJ,HH HYKJ1ea3aMH.
Oco6ennoro sm1Ma1-urn Tpe6yeT H3Y'leHHe BHpycoB·CaTeJI· JIHT0I3 ,I1JiK-co,nep11,amax (.D.eneH,noBnpycbI) H PHK-co JJ,ep2KamIIx (.Ll.CJlbTa-BHpyc). floHHM3HHe MCXaHH3Ma B33HM0· J].CHCTBHH HX C BHpycaMH-II0M0ilJ.HHK3MH HBJIHeTCH ycJI0BHCM
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HaHMeHee CilCIJ,lHfll!lICCKH}! yaeJI BHpycHIIJl.YUHp0B3HHbIX cmr Te30B, He cHrnTaH Tpauc.1JHUHIO MPHI< 3ymrnopnannpycoB 11 K3JIHll.HBHpycoB• .UeHCTBHTCJ1bHO, y II0J].3BJ15ll0Ill.Cf0 60,lhlllHH·
C'l'Ba BttpycoB MPHK HMefOT TaKyro >Ke crpyKrypy, KaK H KJie TOlJHbie MPHK, l!X CTTCUHqJHlJHOCTb 38,ll.aeTCH TOJlbKO reHen, lJeCKHM KO,LI.OM. BepOHTHO, ML,[ He CKOpo CMO:lKeM IlOBTOpHTb npttpOJJ.Y, HaHJJ.H TaKoti ToHKHti 1v1exa11H3M, KOTOpb111 ace Me «yMy,llpHeTCH» (JJ.pyroe c.noao TPYJ.lHO npttJJ.yMaTb, lIT06bI BhI pa3HTb YAHBJieHHe H socxttmeHtte MYAPOCThIO npttpOAbI) oT JIHtJBTb co6cTBeHHhre MPHK OT t1yMepOJJ.Hb1x. Kor.ua Mb! rron MeM so scex ,n,eTam.1x, KaK HI-ITeptj)epoH3To «JJ.eJJaer», ror,n,a, E03MO:lKHO, HBH,ll,eM H ero aHaJIOfH. rioKa Me rrpH,n,eTCH ,ll,O EOJlbCTBOB3TbC5l upttpOj!,Hb!Ml! HHTepqiepoHaMH H HX HH.LLYKTO paMH, H TBKMe rrperraparaMH, rroJJytJeHHbIMH MeTO,ll,3MH reHHOH 1rn:m:eHep1rn.
ILorroJIHttTeJibHaH 3a.n.aqa - ITOHHTh, KaK noJIHOBHpycb1 H KaJIHUHBttpychI o6xo,n,HTCH 6e3 K3IT-CTPYKTYP, npttcnoca6JIHBaH pH60cOMHble CHCTeMbJ K pacn03H3B3HHIO BHpyccneUHQ)H'leCKOH HH<µOpMaUHH H ,ll,HCKpHMHHHpyH co6cTBeHHY!O, KJieTOlJHYfO, Ha KOHeu, oco6011 3a,n,at1e11 SIBJISieTCSI IlOHHM3HHe MexaHtt3MOB 110,ll,BBJieHHSI BHpycaMH CHHTe3a KJieTOlJHblX MaKpOMOJieKyJI - ILHK, PHK H 6eJJKOB. B o6rueM 3TOH ¢YHKUHe11 06J1a)l,a10r 13HpyccrreuIIQ)HlJeCKIIe 6eJJKH, KOTOpbie H8XO,ll.SITC51 B COCTase BHpHOHOB IIJIII CIIHTe3IIpy!OTCSI 13 ree1em1e 13HpycIIOH 11Hq:JeKUIIII. BeChMa B8:lKHO cneUHq:JIIUHpOB3Tb 3TH 6eJIKII H ITOHSITb Mexa HH3M HX J].CJ1CTBH51 Ha KJleTKY, C TeM lJT06bI I!Jlll HCK8Tb HX aHTH.LLOThl, HJIH 6JIOKHp0B3Tb HX CHHTe3 II rpattcrropT B 51,D.pa H K ptt6ocoMaM.
BttpycHb1€ 6eJJKH nperepneaaIOT IlOCTTp3HCJI5IUHOHHblH npo uecCHHr - rrporeoJIHTHlieCKoe Hape3aHIIe s11pycHhIMtt 11 KJieTotJ HbIMH nporea33MH, fJIHK03HJIHp0B3Htte, cpoccpopttJIHpOBBHIIe, MeTttJIHposaHHe II .up. Y:lKe cett'!ac 3TH npouecchI cra.ntt rrpe,n, MeTOM T3K H33hlBaeMOH Herpa.LLHUIIOHHOH XIIMHOTeparrtttt BII PYCHblX IIHtj)eKuIIfl. TaKoe HatiaJio IT03BOJIHeT ua.ueHTbCH Ha ilepcrreKTIIBHOCTb pa3BHTH5l 9THX HarrpasJieHHH.
<I> o p M H p o s a H II e 13 II p H o H o s. ILJrn H30MerpH'!eCKHX H naJIOlJK013H,ll,HblX B11pyco13 xapaKTepHo ¢opMHp0B3HHe BJI pHOHOB nyTeM caMoc6opKH. TTpH 3TOM MexaHH3Me B33HMO.LLeH CTBH51 6eJIKOBbIX MOJieKyJI, a T8K:lKe 6eJIKOB C HYKJieHHOBbIMH KHCJIOTBMH o6pa3yIOTCH crpyKrypbI c MHHHMaJibHbIM ypoBHeM cso60,ll,Ho11 3Hepnrn. TTo 3TOMY .>Ke THITY rrpo11cxoJlHT c6opKa HKOCa3,n,ptttJeCKHX 11 13HHToo6pa3HhIX crpyKTyp HYKJieOH,ll,OB o60JIO'!e'!Hb!X BHpycos. TTp11 CKOTTJI€HHH B KJieTKax (s Sl,ll,pax, UttTOnJia3Me) raKtte crpyKrypbI cpopMIIpy10r KpttcTaJIJIOo6pa3Hbie peweTKH.
Ka>KercH O'!eBH)J.HbIM, eno ,ll,aMe npttmumttaJibHO He cy ruecrnyer cnoco6os, npenHTCTBY!Olll.HX caMoc6opKe srrpttOHOB H HYKJieoKaTICH.LLOB, O,ll.HBKO 9TO, sepOHTHO, He COBCeM T8K H
3TO MO.tKHO BH,11,eTb Ha rrpHMepe caMoc6opKH BHpHOHOB ITOJJHO BHpyca. ,Ua.tKe B IJYBCTBHTeJJbHblX (rrepMHCCHBHbIX) )l_JlH ,11,aH Horo BHpyca KJleToqHHX KYJlbTypax HapH,11,y C ITOJlHOUeHHHMH BHpHOHaMH, B KOTOpbIX KaITCOMCpbl rrpe,11,CTaBJJHIOT co6ofI
ITJJOTHO yrraKOBa11Hb1e cyrrpaMoJJeKyJJHpHbie CTPYKTYPhI 113 6eJJ KOB pOaTpOHeBcymecrnyIOT B11p11OHb1 11 oco6eHHo IJacTo rry
CTbie KarrCH,11,bl, r,11,e MOJJeKyJJbl 6eJIKOB 6oJJee pb!XJJO yrraKoBa Hbl B cyrrpaMoJ1eKyJ1HpHb1e CTPYKTyp1,1. 3To, rroMHMo rrpoqero, o6ycJJOBJJHBaeT OTJJHIJHe aHTHreHHOH CTPYKTYPH rrycTHX Karr c11,11,OB OT TaKOBOH ITOJJHOUCHHbIX 1mpHOHOB. Pa3pb!XJ1em1e Karr COMepoB C 113MeHeHHeM l!X Komj>opMaUHH Ha6JJIO,l],aeTCH TaK.tKC rrp11 B3aHMO,ll,eHCTBIIll BI!pIIOIIOB IIOJIIIOBIIPYC3 C UHTOITJJa3Ma THlJeCKOH MeM6pa11ofI B rrpouecce rrpOHHKHOBeHHH B KJJeTKy. 3,11,ech He MeCTO ITOBTOpHTb, HaCKOJlbKO CJJO.tKHbl H corrpH.tKeH Hbl rrpouecChl caMoc6opKH BHpHOHOB ITOJJHOBHpyca, OTMeTHM Jllllllb, lJTO ,11,a.tKe KOJJHqecTBellllbIC HapyllleHirn B COOTHOllleHHH CHHTe3a HeTa11 6eJJKOB MoryT rrp11BecT11 K cpopMHpoBaHHID HerrOJJHOUeHHHX BHpHOHOB C ITOHH.tKeHHOH HHcpeKUHOHHOCTb!O.
THCBeTe rrp11Be,11,eHHbIX ,11,aHHbIX BO3MO)KHOCTb BJlHHTb Ha rrpoueCCbl caMoc6opK11 BHpHOHOB He Bb!LTJH,11,HT CTOJlb Y.tK cpaH TaCTHqHoH.
BJIHJIHHe ua rrpoueCCbl <jJopMHpoeattHJI o60JI04ClfHblX BHpy COB. 3To BJIIIHHIIC cu e 60J1ec BO3MO)KHO Ha cpopM11poBaHH(:' B006lll,e BCCX 1rnpycOB, B TpaHcrropTe KOMI1OHeHTOB KOTOpb!X KJJeTKa aKTHBHO yqacTByeT. eHpoJJH UHTOI1JJa3MaTHqecKHX l:l BHyTpeHHHX MeM6paH CKa3aHO Bblllle. Ho 3TO B HeMeHhllleii CTerreHII OTHOCHTCH II KO BCeH CIICTeMe BHYTPHKJJeTOlJHblX CIIH· Te3OB (CB060,ll,Hhle, MeM6paHOCB513aHHhie pn60COMbl, MHTOXOH ,11,p1111, arr11apaT foJJh,ll,)!{11), a T3K)Ke BHYTPIIKJJeTO'IHOro TpaHcnopTa.
Ko H T p O JJ b u 11 T o r r a T 1IJ e c Kor o , 1 1 ,fice T B HR B H P y C O B. 3To BJJH5111He, ITO-BII,11,IIMOMY, MO.tKeT TaK)Ke KOHTpo JI1IpoBaTbC51 pa3HOro po,11,a B03,ll,eHCTBH51MH KaK Ha BHpyCbl, TaK H KJJeTKII. BK,11,pyrofI CTOpOHbl, 3JllIMHHaUH51 nopa.tKeHHhIX BHpycoM KJJeTOK MO)KeT T3K)Ke CTaTb O,11,HHM H3 MeTO,11,OB He Tpa,11,HUIIOHHOH TeparrHH BHpyCHbIX HHcpeKUHH, II B 3TOM CMbIC Jie 11OJJO)Ke1111e «y6efI KJJeTKY, nopa.tKeHHYIO B11pycoM», MO.tKeT HMeTh He Mellhllle CMbICJJa, lJeM HHrH6HUH51 HJIII YHHlJTO.tKeHHe caMoro BHpyca.
IlocJre TaKHX o6lll,HX coo6pa)KeHHI1 ITOCTapaeMC51 ITO,11,BC CTII KpaTKHe IITOrll TOMY, lJTO y)Ke c,11,eJJaI-Io B XHMHOTepanHH Bnpyc11bIX HHCpeKUIIH.
pKCOOTBeTCTBHII C KJJaCCmp11Ka1 HeH r. TeHra,1er0Ba (TOaHeK Belll,eCTBa aHTIIBHpycHoro ,ll,CHCTBl151 MoryT 6h1Tb pa36JIThl Ha rpynnbI.
TeHa
K I-ii rpynne OTHeceHbI aHTH6110THKH nma aKTHHOMHUH· Ha D, nypoMHl).HHa, MHTOMHUJrna; 3HOM3J!bHbie HYKJieOTlf)lbl THITa KOp,ll.HUe11HHa, UHT03HH-apa61rno:rn)la, qnopypHJI:Hfla; TOK CHH 3Jlbq:>3-aMaHHTHH H .ll.P- 3n1 Bemecrna OKa33J1HCh TIOJIC3Hb!Mlf ,LVUI H3ytieHHH BHpycHH/l.YUHpOB3HHLIX CIIHTe30B, HO OHH He CT3JIH npenapaTaMH /f.JIH XHMHOTCpamm rrnpycHbIX HHq)e1< u11i'1 113-33 BblCOKOH TOKCH'-IHOCTH. Bo 2-IO rpynny Bbl,llCJ!CHI,J 3HTIIBHpycHble BemeCTBa C orpamftICHHhl:VfH, HO Bh!pa,KeHHbIMH XHMHOTepaneBTH'ICCKHMl! CBOHCTB3MH. He3-it rpynne OTHCCCHbl npenapaTbl, KOTOp1>1e HCIIOJlb3YIOTCH B 11paKTHKe: 3M3HT3)ll!H H peMaBT3;1,lfH, Men,ca30H, 3l).CIHIHapa6HH03HJl (Ta6.n. 20). UeJ1ecoo6pa3HO KOMfornupOB3HHOC ITflHMCHCHHe XHMHOTepa ITCBTH1ICCKHX rrperrapaTOB, ycHJIHB31011..f.ee JlCllCTBHC K3)KAOrO 113 HHX B OT)lCJlbHOCTH.
pOB6 .11 HuyH eHpHCpe11,cTBa .11e•1ett1-1R onpyctt1,1x |
60.11e3HCH |
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TIpenapar |
3rpnOKTpoan). .nMCCPBHBtnyb. |
aycoHepHB |
,3H(0rnBpa.1HHce1Kae'o,OcI. |
. |
PacreopH.Mhlii peuenTop CD4,
.neKcrpau cyJ1bcpar H .np. AMaJ-ITa)J.HII, peMaHTa)J.HH
Vlo.!l.!le30KCHypB)J.IIH, a.neHHH· apa6111-I03H.D;, UHT03I-IHapaGH-
1103H;J., aUHKJJOBHp, pH68BH pHH (B11pa30JJ) H .npyrne aH0MaJII,Hble HyKJie031i./lbl A3H)J.OTJIMll.!lHIJ, 2', 3'-.!lll}lCOK CIIHyK. C03H.!lb!, cpoccjJoHo(jlop
M8T H AP TaoceMHKapoaaom,1 (Mernca3oH)
Hnrep<j1epoa
I1oJJH (H)-(TJ,), 0OJIH (/\)
(Y), JlBYHHTeDb1e PHK H .np.
AJJ.coptfam1 |
Bttpyca |
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na |
KJJeTO'IHOH TIO· |
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aepXHOCTH |
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BHpychl rpmma |
A, |
Pa3)lesaime m1pyca |
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3JlbQ)3-BHpycbl, ape |
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HaBHpychl |
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Penmmaum1 |
HYK· |
fepnecBHpychl, |
BH |
JICl-lflOBblX KIICJJOT H |
pycw rpttnna M MHO |
HX |
rpaHCJ(pHnUHH |
rne .npyrne rpynnw |
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BHJ>YC0B |
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O6parna.n |
Tpanc- |
O1mom1pycb1, BHLJ |
KPHTI!lllli |
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TpancJIHl\Hll |
MPHK |
Bnpycw ocnbl |
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To )Ke |
|
Mnorne nupycw |
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Hn.nyKTOpb1 |
HHTep |
To }Re |
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cjJepo11a |
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XHMHOTepamrn HeaHJ( H ee nepcneKTHBbl. CT a ,ll. Ii 51 a A - c o p 6 U H H H n p O!iHKH OBCH H H 13 !UI CT K y. Ha'-laJibHOll
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cra,1:01e11 B33HMO)leMCTBJI51 BHl..J: c KJieTKOH HBJrne-rcH ero npH |
Kpen.nem1e K KJ1eT011HoMy peuen-ropy |
CD4. Tipouecc cneuH<pH |
,,ecKoro CB513bIBamrn |
peuenTopa |
C |
HC60JiblllHM |
y11aCTKOM |
gp 120 MO)KCT rrpeJlCT<lBJUITb co6011 MHlllCHI, J .;151 aTaKI! |
a!ITH |
TC.l3MJJ II XHMHOIIperrapaTaMH, a |
T3K}Ke |
He60JibrITl!MH |
ITCfITJI· |
l).aMn, 6.10Enpy10111.11Mu |
cooTBCTcTBymmyFO |
06.rracTb |
peuernopa |
tfJIII gp 120. MoHOKJIOH3JlbHble aHTI1TCJ13 np0THB M0JleKyJlbl CD4 npe;wrnparna10T 06pa3osairne CHHIU1TIIH 11 6JIOKHPYIDT
lllHpeKUlllO. Tio-BH,l]JIMOMY, mo6oe II0BpC}K)I_C[Ule IJJIH M3CKH pQBKa K.TICTOtJHb!X peuernopcm 6y.nyT Ilj)CilHTCTB0BaTb H!)0HI-!K HOBCHIHO B KJJ('TKH BIIpyca, rrornrnmero B opralIII3M H3BHe HJ!II npo.nyn11pyeill0ro 3apa,KCHHb!Mll KJ]CTKaM!!.
B ue.rrnx npe.nornpau.1.e1rnH CBH3bmamrn s11pyca c KJ1ernq HOH f!0B('J)XH0CTbIO MoryT 61,1Tb l!CIT0Jih30133llbl TaKHe mmo
TJ)0IIHble 13CIII.CCTI33, K0T0!)ble Cll0C06Hbl H3MCIU!Tb JIH!UIJJ,Hb!H COCTaB nnpyca !!JIil KJICTKII, 8 T;Jl{i[((' llclJ)YlllIITb KOHlpopMa[lHIO BHpycHoro npHKpenHTCJII,H0ro 6cmrn JUUi C00TBCTCTBCHH0 KJie T0lJI-!Oropeuc1nopa. C 9Toii }[\C llCJl!,10 MOiKJ-10 IICII0.'lb30133Tb M0HOKJIO!IaJlbllb!C aIITllTCJHI K gp 120. BII.UllMLIM npenHTCTBHeM
.ll,JI5I !IX npnMeHemrn 51BJI5ICTCH lllllj)OK351 Bapna6e.1bllOCTb 6eJ1K0B env. O.nnaKo H3MeHemrn B yTiacrKe, y3Ha1on eM peue1nop CD4, n yqacrn:e, ocyll!ecrnmnon.1.eM cmrnm1e MeM6paH, orpaHH lJCHbI, 9TO J-I3H0OJ!Ce K0HCepBaTirnlll,Ie o6JI3CTH 6eJIKOB 060• JIOl[KlI. TI09TOMY MOHOKJIOH3Jibllb!C aHTHTeJla, fl0JIY4Cl!Hble npo THB 9THX giparMCl!TOB, ,l],OJlJKHbl CB5I3bIB3TbCH II He1ITpa.'lll30BaTb 6oJibWHHCTBO !130.;lHT0B BHpyca.
Tio,a,xoJJ, K 31fTIIBI1pycHoii Tepamm, OCHOBaHHbllI Ha 6JIOKll· poBaHHll KJICT0T1HblX peuennipoB C II0M0lljhIO M0H0KJ!OH3JlhHblX aHTHTC.!l, 0C.JI0}KIICII TCM, 11'!'0 clHTHTCJJa, 6.'l0KHpy10mue pe uenTop CD4, GyJLYT mrn31,11rnT1, He6J1arorrp11HTHoe .ncJ1cTBI1e na <py1mumo T4-JmMcjiounTOB, nocKo.rll,KY CD4 HBJIHeTCH perI.enTo poM JJ,nH 6CJil{0B KJiacca II 0CH0BH0ro aJ-IT!lreHa rl!CT0C0BMC· CTl!M0CTH. TTepcrreKTHBHOC IICII0J!h30BaJ!Ile aHTHH}],H0TiaTHt!e CKJ-IX aHTHTC.11, T. e. 8HTHTC.'l K 3l!Tl!TC.'l3M 11p0TIIB peuenTopa CD4, K0T0]H,Ie uMnrnpy10T CTpyKrypy peuemopa CD4 H cno co6Hbl B33JIMOJLeHCTBOB3Tb C BHPYCHblM np11KpemITCJibHblM 6eJIKOM gp120.
OTCYTCTBIIe BHpyc11e1hpam13y10me11 aKTIIBJ-I0CTH aHTl!TeJl, o6pa3yIOII\HXCH y 33pa}l{CHHbIX 11 6om,Hh!X Cfll1n JIHU, HH0rJJ,a o6nHCHHeTC5I HX HCCilOC06HOCTbIO 6JTOXHpOB3Tb 6eJIOK cnmrn1rn Ii npe.nornpamaTb o6pa30Ba11He c1rnuHrneB. TiocKOJibKY Bl1'4, KaK 11 .npyrne .1eHTHB11pycb1, cHoco6en pacrrpocTpa1rnTbCH H3 KJ1CTKH B KJICTKY, MHHYH MC}KKJICT0l!H()C npocTpaHCTB0, nep CIICKTIIBHO llCITOJib30B3Tb rrpenapaTbl, 6JIOKHJ)YIOllJHe KJICT0IJ Hb!H peuerrTop CD4. C 3TOH ue./Jbm npmvreHRIOT c111-rreTHlJCCKHe omffonenTH,ll,bI - aria.11orn ytrncTKa CD4, K KoTopoMy npn KperwHeTcH gp120. Pa3pa60Tall 6HOTCXHOJ!OrHIJCCKH11 MeTO,LI, rroJ1y'!eHHH pacrnopHM0ro peu.emopa CD4 (pCD4). C 9Tm'i uenh10 11cn0Jlh3onaH reH CD4 c y)]...rnem11,11,rn noc1e.nonaTeJ1b HOCTHMH, K0JUIPYIOlljlfMil TpaHCMeM6pm111y10 II UHT0fIJia3M3TH· qecKy10 o6JracTb M0jJeKym,1. PeKoM6H1-1aHTHbJH r.'lHKonpoTellA,
COJI.Cp)KallU!tI 368 aMIIHOKHCJIOT!lblX OCTaTKOB, 06.riaJI.aeT 8HTil·1 BIIpyc1rnrr aKTl!BHOCTblO, MCXaHil3M m1n16111urn 33K./l!Ol!3CT(.:Si' B rrpHMOH KOHKypeHUHII 33 CBH3hlB3HIIe gpl20 II 6JIOKI!p0Bij mrn a,a_cop6um1 BHpycHbIX 1iacn1u Ha KJieTOIJHOfi noaepxHoc'in [Smith D. ct al., 1987; Fisher R. A. et al., 1988; Hussey R. E. et al., 1988; Dean K. C. et al., 1988; Traunecker A. et al., 1988].
Ilpu 0,[],HOBpeMeHHOM JI,06aBJICHIIII npenapaTa II B114-1 K 1IYBCTBHTC.'lbHblM KJICTKaM )],JIH m1rn6upcmaIIH5I l!HtpeKIJJfH Tpe6yeTCH 66JII,ll!a5I KOllllCHTpauirn npenapaTa (7 HMOJ!b), 'ICM npII npemrnpHTCJibl!OM KOHTaKTe c BHpycoM (0,5 HMO.'lb) [Byrn R. et al., 1989]. B npHCYTCTBIIH rrpenapaTa, KpoMe TO· ro, Bnpyc TepHCT MOJICKYJ!bl gpl20, B03MOJKHO, B CB5I3lI C o6pa30l3aHHCM KOMilJJCKCOI3 C pCD4, l!TO T3K}KC rrpHBOJU1T K yTpa TC 1mcj1eKUIIOHHOJ:i aKTHBHocrn. I1mPeKUHH 6noKHpyeTcH JI.a)Ke npH ,a_o6aBJ1CHHII npenapaTa nocn.e a)l,cop6u1rn Bnpyca B pe3YJihTaTe npe,lI,OTBpanLeH!IH CJII1HHilH Ka1CTOK lI pacnpoCTpa11e HHH BIIpyca. TipenapaT no)],aBJIHCT TaK}KC l!HCpeKUHIO, Bbl3B3H HYIO B114-2, HO )],J1H 3TOfO Tpe6yrorCH 6once Bb!COKIIC KOH uell'rpaum1. BoJibUIHM rrpeHMyll!,eCTBOM rrpcnapaTa 5IB.115IIOTCH OTCYTCTBHC 6JIOKHpoBaHHH y11acTKa, Y3H3IOI1Lero 6eJIKII KJI3C ca II lv1HC, H coxpaHe1rne cpyHKUHOHaJibHOI':i aKTHBHOCTII T4-JIHMq>OUHTOB [Larnmare D. et al., 1989]. Ycneurno npono A5ITCH 1mrpOKHe KJJllHI!(!CCKIIe HCilb!TaJUrn npcnapaTOB pCD4.
,Upyrne c1rnTeTuqecKHC nerrTH,ll,bI, coOTBercTByronv1e onpe ,a_eJieHHbIM o6JracTBM CD4, T3K2KC crroco6HLT OJIOKHponaTh BI14-HHCpCI<UHIO ll npe,a_ornpall!,3Tb o6pa3oBaHHC CHHUHTHH,
fierrTI!Jl |
]13 |
12 aMHIIOKHCJIOTHhlX |
OCTaTKOB (OT 81AO 92-ro) |
IIOJIHOCTb!O |
6JIOKHpycT CIICilHq)l!'IeCKOC B33HMO,[],eikTBIIe BI14 |
c CD4 |
[Lifson J., Engleman E., |
1989]. HpH 3TOM y,a_aJie1rne |
N-Kom1enoro 0CT3TKa Tpeomma ycTpa!IHCT IIHrJI6HTOpHbIH 3Q) q>CKT. TioHB.15IIOTCR rrpenaparh1 CD4 BToporo rroKo.r:1eHH5I. fH6pII,a_HhIJ.i 6e.110K CD4 + IIMMyHorno6ymrn coxpamreT aHTHB11pyc ny10 aKTHBHOCTh in vitro, HO npno6perneT cnoco6HOCTh K AJIH· TCllbHOii IUiPKYMIUIIH [Capon J. et al., 1989]. fipenapaTbJ CD4 npeJLOTBpamaror pacrrpocTpaHeHHe HHq)CKIUIH, HO HeCHO· COOIIbl pa3pymIITb 3apa2KeHHY10 KJ1eTKy. C ::non 1.i:enb10 noJiy lia!QT 1<011HoraT CD4 c 3K30TOKCHHOM, narrpHMep c A-uenbro pmuma [Till M. et al., 1988] IIJIH c 3K30TOKCHIIOM Pseudo monas [Chaudhary V. et al., 1988]. CD4 B ,ll.airnoM c.riyqae CJiy:HrnT ,ll.JLH llOl!CKa MliIIICHH II CCJ1CKTHBHOror UIITOTOKClI(!CCKO ro sitpq)CKTa nporHB KJICTOK, EmcrpecCIIpy1oll!,HX gp120. Ta Kile areHTbl MOryT ceneKTHBHO y6HB3Tb 3apa)KeHHbie KJICTKH TH na MaKpotparoB, KOTOpLIC BC ru6HYT OT UHTOTOKClJllCCKOro llCH· CTBHH 1rnpyca.
JJeqe6HblM )1.eikTBHeM npn CITHn 06Jia)l.aeT p.H)]. rrpena·anm, ,LLe1krny10w.11.x ua mIpycny10 oGoJJ0lIKY u KJlCT0lJHbie f\\eM6pa111>1. K 1rnM oTH0CHTC.H ,neKCTpaHcyJ11>cpaT - cyJ1h<p!ipO· B HHhlH II0Jl!ICaxapH;JJ, c MOJleKyJrnpl!0ll MaccoH 7000-9000, JiIC}1:0Jlb3YeMblH B MC,LI.HUJIHCKOH npaKTHKe Jl,,'I51 CHlDKemrn ypoB• Hll txoJICCTepm-ia. ITpenapaT GJIOKHpycT o6pa30BaHHe CHHUHTllll H n pexo,11, BHpyca H3 KJ1CTK11 B KJieTKY, npernncTByer CBH3bf· BaHHJO B1-1pycac peuenTOp0M [Jarchoan R. et al., 1988; Tochi kura T. et al., 1988],.O)1.HaKo on He npomrnaer qepe3 reMaTo· 3Hll.CQ)3Jlll'4CCKHH 6apbep. McKa;1,0p (3KCTp3KT pacTCHHH CB· ponefiCKOH OMeJib!) T3K}l{C GJ101rnpycT o6pa30BaHHe CHHUHTHH H pacnpoCTpaucttue mIpyca. BHT (GynumpoBaHHbIH rH.LI.p0K· CHTOJ1ye11)- aHTII0KCII.ll,aHT, IIC!10Jll,3YCMbiii .ll,JIH K0HCepmrpo namrn )K11p013 H MaceJI, HH8KTHBHpyer JlHilH.LLC0,!l.Cp}l{aUlHC BH· pych1: npocToro repneca, UHT0Mera.TJIu1, ;1ecoa CeMJlHKH, 60JiesHli Hb10KacJ1a u Jlp. Al721 npe,LI.CTaBJJHer co6oii cMech HeihpaJ1bHLix JlHHHJl.0B, c)_Joccpanuu1J1xomrna 11 cpoccpanuJ.HJI3TaHoJraMHHa. Dpcrrapar ACHcTByeT Ha JIHHH,D.bI o6oJioqKH BFI pyca H KJICTKH, ynaJIHH X0JICCTCPHH H TCM caMblM Hapy111aH 1paHcMeM6pauHoes., npom-IKH0BeHHe BHpyca [Mitsuya H., Bro der 1988]. HeKOTop1,1e npenapan,r MoryT CCJICKTHBH0 ,LI.CH· crnoBaTh Ha peuemop CD4. AypmnpnKap60KCHJ10BaH KHCJI0Ta ceJJeKTHBH0 6JIOKHpycT CB513bll3aHIIe M0H0KJI0HaJlbHhIX 3HTHTejl c CD4 Ha II0UCpXH0CTH Jl!IM(pOil}lHblX KJICT0K H nperrnTCTBYCT CBH3b1Ba11nKJ B114 c LfYBCTBHTC.TibHbIMH KJICTKaMH [Schols D.t al., 1989]. faHrJIH03HJJ. GMl rrpH ,LI.o6aBJiemrn K KYJihType JIHMq:>OH,Ll.HhlX KJICT0K npHB0,AHT K CCJleKTHBH0My HClfe3H0BCHIHO
CD4 c |
KJ1eTo,rnoii noBepxH0CTH H y1pa1e 'lYBCTBHTCJlhHOCTH |
K B114 |
[Offner H. et al., 1987; Chieco-Bianchi L. et al., |
1989]. |
|
flpH 0TMblBSHHH raHrJJH0311,Qa M0JICKY,'Ibl CD4 6bICTpo B0C |
CTattaBJIHBaIDTCll Ha KJ1ero1rnoH rr0Bepxnocr11. Hanponm, JIH· fl0C0Mhl 0K33hIBaKJT rrp0TllB0II0,10)KH0e ,ll,CHCTBHe: 6Jial'O,ll.3p5I HX ,LI.CCTa6HJl11311py10w.eMy BJJH5IHHJO Ha KJlCTQqHhre MeM6paHb! 0HH cnoco6Hhl YBCJIHLfHTh 3q)q_)CKTHBHOCTb np0IHIKH0BeHHSl BH pyca B JIHMcpon.nttym KJ1CTKY. TTyre1v1 .L1.06aBJ1eHH5! JIHnocoM, noJIy1IeHHblX H3 HJilIH0ro 6eJ1Ka, K J1111v1qioun1apnb1M KYJihTY paM HaM y)J.aJI0Ch 3Ha1ll!TCJlbH0 II0Bb!CHTh 3qJ¢eKTHBHOCTb npo HHKH0BCHHSl 1rnpyca B KJICTKH Fl ero penp0.LlYKUHl0, onpe.ne J1.HeMy10 110 K0JIHlJCCTBY BHpyccneumpHl!CCKHX fl0CJIC,ll.0BaTeJib
HOCTei-i B sapa2KeHHb!X KJICTKax C IT0M0!llhfO Tol!elJHQH rn6p11- Jl1-13aUml [TeHUOB IO. IO. H JlP,, 1989] (p11c. 14, c. 214).
Cmrnttue a11pyc11oii 06onol1KH c KJICTOllHOH MeM6paHofi co npoaoIB)].aeTcH BblX0,LI.0M B UHT0IIJ133MY BJ-IyTpettHero K0MTI0· HeHTa a11pyca. llpo:u.ecc «pa3.11.eaaHHH» B114 113yYeH nJroxo.
1982; Riggs R. et al., 1989]. Hen3BeCTHbI pom, H J101<aJJH3a i.),11.SI I3 IrneTKe 6eJma p 17, 13b!CTHJl8JOUI_ero JIIIIIOIIJ)OTCII.UHYIO OUOJl01IKY BIIpyca C BIIyTpeHHci-iCTOpO!lbl. 011 MO.tKCT y.uaMITb Cfl C rronepXHOCTH eupyca BMCCTC C 6cnKDMH o60JJ04KH JJH60 BUXO,ll.HTb B UIHOUJJa3MY BMCCTC C cep,nu,eBl-lHOHH y;'"(aJUITbC51 tta ornpoii cTa)lHH «pa3AenaHirn». ITpo11,ecc«pa3,nenaimm) 3a rpy;u-1e11113-33 6oi1cc CJIO}IOIOh opraIImau.m1 nuyTpettnero KOMTIOHeHTa BHpyca H H3JIH4HH 6enKa Kancynw cep,nu,eBHHW p24. HcH3Bec-rHO, Ha KaKoii CT3,ll.llll «p33ACB3HH51» rrpoucxo
.UHT ero y 11.aneIme Ii BblCR060)K,ll.CII!lC HYI{JICOl<:JllCH/.l3Bee. 3TH npouecCbl TIOCJle BX YT01IHCHIIH TaK)KC MOl)'T 6bITb MHlllCHbIO
,nJrn attTHBHpycuoti Tepamm. |
C T a .u |
H 51 0 6 p a T H O 11 T p a H C K p 11 II 1( H If 11 H H T e - |
r p a u, H 11. |
fe110MHa51 PHK B cocTaBe HYKJICOKancHJ a cny)KHT |
MaTpH11,e11 ,ll)HI 06panwf1 Tj}3HCKJ)HllllIHl. 3Ta CTa,ll.Hfl npe.u CTaBJl51CT COOOH Tij)!!B.JJCK8TCJTbHYK) MlUllCHb ,ll.JHI XHMHOTepa
lUIH, T8K KaK |
B03MO)l{Ha ,ll.[lCKpl1MHHaU,H51 Me}l{J.l.Y o6paTHOH |
TPaHCKpttnuncH |
H KJ1eT01ll!blMJ1 llOJIHMCj)33HblMH peaKU,H51MH. |
K ToMy }l{C MIIOroe H3Becrno o cnoiicrnax H ¢ynK1 HH nnpyc HOH o6paTimi:\ TpaHcKpHnTa3bl, a C ITOMOll.lbIO JJ.PO)K)KeBbIX H 6a1ncp11aJibHblX 06pan1LIX TpaHCKj)HIITa:-i B114 MO}KHO npo BCCTll CK))llHJJIIr 3HTJ!BllpycHhlX npenapaTOB. 06paTH351 TpaHC· KpHnTa3a BvP-I, COCT05lll.l3ll ll3 JU3YX cy61,CJ].HIIHU, p51 II p66, HCITOJib3YCT Jll13I1110£3ym PHK B Kalfecrnc 3aTp3BI<H flJlH CHH· Te3a 11rnI1yc-m1TH JlHK. B o6pa3yKJll.lCMC51 JtHK PHK-rn6- JJH)1-C PHK pa3pymaeTc5I 6J1aro.uap51 m<THDHOCTII PHKa31,1 H, accoun11poBaHHO}l C C-KO!H OM MOJICKYJibl o6paTHOii TpaHC Kj}HITT33LI. 3aTeM o6paTH351 Tj}aHCKpH!lTa3a KaT8JIH3HpyeT o6pa30Batt11e BTOpoi'\ HHTH (n.11mc-HHTH) JJ,HK c 06pa3ona HHeM .l(BYHHTCBOH JJ,HK, MHrpHpyK>mei'I IJ K.1 IeTOl!ttoe n,upo. floJI)"ICHLI H anpo611poB3Hbl MHOnIC npcnapaTbl, CIHl)K3!0ll.llle aI<THBHOCTb tjiepMCHTa (cypaMHH, HPA-23, q1occpoHO(j)OpMaT H .up.), KOTOpble npHMCHHJIHCb )(Jl51 Jie11eHH5l ,npyrHX BHPYCHblX HH(flCKll,lH{11Jlll C03,!l.a!lhl 3a110BO. Ha1160J1ee nepcneK'rHBHbl .UH· J].eOKCHHYKJleOTH/.l,bl, OJ.I_HH 113 KOTOpblX, 33H)(OTHMH,ll.11H, flBJ151eTCH ca.Mb!M pacnpocTpaIIe1-rnbIM npenapaTOM ,UJJH netJCHHH Crll1)l. 2', 3'-JlHJ.l.COKCHHYKJIeoTH.UHbIe a11anorn (,11.11,neoKcH a.ueH03IIH, .UH.UCOKCHUHT03HH, ,UH,ll.COKCHHH03HH, S3HJ].OTHMH
.UH1·1) CO)(Cf))IWT XHMH'leCKH MOJ].lHj.JHUHpOB3HHblH caxapHblii KOMnOHCHT 11 HHI'H611py10T penJTHl<al(H!O BI11.l .UBYMH nyTHMH: KOHKypnpyH 3a CBH3blBaime c cpcpMeHTOM uopMaJibllhIX aIIa- JJOfOB H np11 BCTj)31113aHIHI I3 MOJICKyv11y JJHK, HllJIHHCb TepMH
ttaTOpaMH nOJIHMCf)H3aUHll UCllO'IKII ,UHK. I1x KOHUCHTj)3llHH, m-ir11611py1ouu1e perr.1I11Ka1.uI10 n111.1, n 10-20 pa3 HH)Ke Tex,
KOTOj}b!e lJapyllla!OT )KH3HCCTIOC06HOCTb KJieTOK.
CxeMa cj>occj>opHJJHpooaHH!I UH)I.OTHMHJI.HHa H JI.H,ll.eOKCHI\HT03HHa |
A:rn.n.uTIIMHJl.!lH |
|
THMH)JJIHKIIH33a |
|
A3T-MOHocpoccj>aT |
|
(A3T) |
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,Il.u.n.eOKC!HJ;HT0311H |
|
Jl,eOKCHil,HT!fJ\HH· |
|
JI.lI.ll-Motrocj>occj>aT |
(MU) |
|
KHnasa |
1 |
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KmoqeBhIM :nanoM B np1rn6peTeHHH npenapaTaMH aKTHB H0CTH HBJJHeTC5I HX cpoccpopH.1ilpOBaI-rne B KJJCTKe KJieT0qHbJMll KHHa3aMH ,ll.0 HYKJie03H,ll.·5'-Tpllq:>OccpaTOB, K0T0pbie np1106pe Ta!OT cnoco61rncTb KOHKypIIposaTb c HYKJICOTH,ll.aMII. Ecmr co0TBeTcTBy10111.ne KB!Ia3bl B KJICTKaX 0TCYTCTBY!OT, npenapaThl He np1rn6peTyT aKTHBH0CTH. )lH,ll.COKCHHyKJJe03H)J.bl cpoccjJOpH Jlllpy10Tc5l. B KJieTKaX C pa3HOH CK0p0CTh!O H pa3JllfllHb!M ll ny T5IMH, Il 3TH sap1rnu.HH o6yc.10BJIIIBaIOT HX pa3HYJO aHTHBH pycHy10 aKTilBH0CTh.
A3H,ll.OTHMH,ll.lfH 6bIJJ CHHTC3HposaH 6oJiee 25 J1eT Ha3a)J. II HCl10JJb30BaJlc5l. KaK HHnr6HTOp penmrna11.HH MbllllHHblX peTpo BHpycoB. Oil 0Ka3aJ1C5l. 3qHj)CKTHBHhIM HHrH6HTOpOM Bl14. A3IIJJ.OTIIMHJUIH no,ll.aBJrneT perrpo,n.yKn.mo Bl14 in vitro npn 3apa2Kemrn Ky.1hTYPhI T-JIHMq:>OIOiTOB, 0JJ.HaKo He lJ.CHCTByeT na y}Ke 3apa2Ke1IHhie npotJ.yn.11py1om11e snpyc KYJJLTypbI. B opra HH3Me 6oJJbHoro CCTH)l npenapaT He MmKeT npe/J.0TBpan1Tb 3apa}KeHHe mrpycoM J1Ill\Hj)OILHTOB 113 l{JleTKH B KJJeTKY H npo
ftYKII.HIO Bttpyca JIHMcpo11.HTaMH, coAep2Ka1LtHMH npos11pyc [Na kashima H. et al., 1987; Smith M. et al., 1987].
11pH J1eqenttn 60JibHbIX CI111)l s rrepsott cTaAHH 6oJJe3HII a3HA0THMHAIIH0M y 60JJbllIIIHCTBa yBeJIII1IHB3CTCH 1IHCJ!0 II.Hp KYJJHPYJOlUIIX T-xeJirrepos, 0l].HaKo BIIpyc npoJJ.0JDKaeT npoll.y n.nponaTbrn, HCCM0TJ)5l. Ha JIC'leHHe. CTpIIMCpHO qepe3 200 AJ-Ieii II0CJJe npIIMeHeHH5I a3IIA0TliMH)l.liHa fl0HBJ!51CTCH YCTOH1IliBOCTb BHpyca K npenapaTy II qMCJIO JIHMQ)OII.HTOB Haq1rnae1 yMellb lII3ThCH. Bo BTOpOH CT3ll,llli 60Jie3Hll rrpenapaT CHH2KaeT 'lIICJI0 CJJyqaeB onnopTyHHCTH'lCCKIIX HH(peKJJ.IIH .H JieTaJibl!0CTb. Ho B npon.ecce JIC1!CHH5I lJaCT0 neo6xo,'l,HMO Cllll2K3Tb il.03Y 113-33 T0KCII'IH0CTII npenapaTa II B03HHKH0BeHHH aneMHH H HCHTpO IICHIIH. Do O,ll.HOH 113 CXCM Jie1ICHH5l. a3IIA0THMHll,HH npHMeHH·
CTCH rrepopaJ1bH0 B K0HllCHTpaium 5 Mr Ha 1 Kr MaCCbl TeJJa KaJKAhie 4 q [Yarchoan R. et al., 1986, 1988]. OAHaKo He
CM0TpH Ha J1eqem1e, KYJJbTYPhl nnpycnp0Ayn.11py101u11x JlIIM· qJOI(IITOB M0JKH0 6hJJIO llOJIYlJHTb B Te )KC cp0KH, 1IT0 H OT HeJJC'ICHblX 6oJibHblX.
