Virus o Logie

Zhoz ‘nSesnong, BIEOIPEW eANPS at ejesipaw aibojosnii, nosaused ulso9© Toate drepturile editoriale apartin in_exclusivitate Edit le” Publicatia este marca inregistraté a Editurii Medicale, find fe logislafia interna ala. Orice valorife Jor acestor legi si a permisiunii edt le pedeapsa. Acest lucru este vala- Indiferent de pe dischete ilor este interzisa si pas reproducere — integrala sau parti mijloace (multiplicari, traduceri, microflmari, transer etc)’ Descrierea CIP a Bibliotecti Nationale a Roméniei CERNESCU COSTIN Virusologie medicala/Costin Cernescu - Bucuresti: Editura Medicala, 2008 ISBN 978-973-39-0637-7 578.7(075.8) nM il ma fara cere Pant ra ALA Redactor o¢ carte: IRINA BELOIU Secretar de redacje” MARIA ELENA NEANT Tehnovedactor: MIMAL STEFANACHE Corector: CORINA GHINOIU. 698338 (Ina) | SUMAR ARGUMENT. INTRODUCERE. 2 1. GENERALITAT! DESPRE VIRUSURI .. 2. TAXONOMIE VIRALA 3. REPLICAREA VIRUSURILOR .. 4. GENETICA VIRUSURILOR ANIMAL PATOGENIA INFECTIEI VIRALE. . PERSISTENTA VIRALA MECANISME ALE REZISTENTE! INNASCUTE IN VIROZi IMUNITATEA IN’ VIROZE.... 10. INTERFERON! 11, PRINCIPALELE SINDROAME DE ETIOLOGIE VIRALA 12. VACCINURI VIRALE con 43. DIAGNOSTICUL DE LABORATOR AL VIROZELOR 14, PICORNAVIRIDAE.... 15. GASTROENTERITE VIRALE. 16. CORONAVIRIDAE .. 17. ORTOMIXOVIRIDAE.. 18. INFECTIA UMANA Ci 19. PARAMIXOVIRIDAE.... 20. ARBOVIRUSURI 21. RHABDOVIRIDAE. 22, FILOVIRIDAE .. 23. RETROVIRIDAE... : 24 WRUSUL, WAINODEFICIENTE! UMANE (HIV/SIDA) . 25. HEPATITE VIRALE. 26. PARVOVIRIDAE... 27. HEPADNAVIRIDAE. 28. ADENOVIRIDAE 29. PAPOVAVIRIDAE 30. HERPESVIRIDAE.. 31. POXVIRIDAE... 32, VIROZE EMERGENTE. 33. BOLI PRIONICE.. 34. VIRUSURI $1 CANCER... 35. MONITORIZAREA TERAPIE! ANTIVIRALE... INDEX .. .eugwioy jawepedy Je uspucdsaico nuqwiory areapoW oun op sawepeay je niqwory ROSOWIeD UNSOD IQ Joly Jalen, ofoouwey 18 eucpoyy ap eajeysienuN ‘ euspoy 8p eajeynae | ‘S002-vO0Z seN'SIeAUN jnue UJ e;nul) e;GoJ0snIA op Jojunsina |nynujtuoo yewnze: ojs0 eyed siew jew kao WY) ‘eseO/fO5;U) aBojored 9p joyideo jueyodut inysede eaytoads so}a}uySouns earezyenjoe wy iJeserejuy ajeyyeioads eye 2ou0 ep nes so}e10qe) ep ‘fusprzes sojopeur 18 eurojpeus uy sojfuepns jeugsep 9js0 \npxoy son 91yBo}ouya} no 40} earepioge wud a}euO/INOs jsoj ne e1e9 swe{qo.d Joun eaiejeuwes 1§ ‘e0/se9 oja}9p EGU) ed ‘puudno jenuew js908 Uy aiewazald opjeuojy -orBo}ouys} @ inseooe ep rezwIUW o}59 eA ul oy nu BS sed e=jOp je e2 nosy “eluNs ‘nsojeuUN ‘e1Bo}oUye) ueeyo 9s jnuese} ezeeuoje} os B1e9 no sed Inuuue) “soUNSE\L 49:0) Un-quy ezeojWeU! 20 10189 eURWeAse as jio}p}eRIe0 29 snds e-G 29 9p auapous soMbo}OUYe} jnjoedW! ap BleaIeW oWWIOINd 4150 2pesap sounn e1Bojosnay, “oyesuene unjeny ul juns eaje}e Boul Jef ‘20 uy uy ejeoyde juns ejeunque op Og a\sed ‘izeisy “someday ajunsnun ed 8 afedu6 aynsryn ad onyoe ajuoweopow enoje9 1e0p nejsixo 0661 us Bue ‘esoeIU! ep yGISOd eu 0 yore B eIN}see e ede}o aye00y Eun ageoydas inynyo; wioBara}u) esnseUI ad “(919 ouLoyBuods edu6 ‘vals ‘een ajamedoy) aeyues Joyeqoine efuaye Beye azo1n oN (ejoelny “eyenuscyod) efuepiou e9 @snpe1 auseip y e 9p ajeo od juns nes (ejoues) sJeoper0 so) ne sowepued glep Bye ezay\ “sojUyD Jo!69jOSRA InjuoWOD wu! snpoid nne-s uequiyes oynus ‘oreiwewepuny iwiedodsep 2}800e no juo}WoouOD (219 doysig ‘snuwen ‘ooveqing ‘yasnpfep ‘Brequinig ‘ujuoy ‘esownyeg) !GojosnuyA oun jor: ne ‘jeAieju! Wyn jse9e wy a}oU ~te09p ‘21bojarz.J 18 euopoy ruyued jaqon meld eyny “aped=p enop ‘}ounin vip axeinoejour 10;6o)01q owezyoe uy ensioep elueyodu o ime © (i6e4) eueyayoeq nes o/2}960n ‘ajeuue soWUNsNUA pms LNAWNONVY perro eneINTRODUCERE Uttimii 50 de ani au produs mai multe schimbari decat cei 500 de ani precedenti, iar ultimii 500 de ani au adus mai mult progres vor putea fi depasit izalia are 50/50 sanse sa sau se poate prabusi precisa concentrajiei virusurilor. Dup& 1970, virusologia devine o cisciplina indispensabi volute’ biotehnologice. Temin si Mizutani si, separat, David Bal descopera reverstranscriptaza - enzima care rastoama dogma cen- tralia biologiei_moleculare. P. Sharp, lucrand cu adenovirusur descopera in 1977 cA genele contin portiuni non-codante (intro alaturi de cele transcrise (exoni) si precizeaza modul de procesar al ARNm prin excluzia intronilor. Descoperirea oncogenelor si a rolu- lui lor in transformarea c (Bishop i Varmus) a insemnat o alta contributie important a virusologi 196 premiul Nobel pentru Medicina si Fiziologie revine lui Dohorty si Zinkemnagel pentru precizarea dublei restric{ii in r&spunsul imun antiviral,[oa uorurysem ‘Zo0z ssid Ws¥ (‘pe) ouoq’eD Wl eseesip yemoyeyaqoinau ur oo! sy pue si 419981 ayeiBouou 0 ep JEIUI]GNS }S0} B NEIOOIN Je “yoypye0129 jfinw yew ap yeBqsan am nes ezoyisd ep ouos Viva naa ay uunsnuiaewiog nd 2 ‘18 (€661-S16L) EledoU0d NpeY “(se6t-C16}) niseuELY eee nosed ‘neIOOIN Ue|aIg ‘NIPEAdT uo!) “ eusznoeueg Ueer cru iyaysnaysed mwa) snojsedd njnimnsu) EAE UL aYSEB y }od oWeO}eIeAe ByUOWNOOP Je1 ‘gueunaysed ejeo0$ | Jewue Ne-s 1ueWO! UojEIe0100 ISOLOWNNY BEDI 129 ‘aueUUE’ gjaseojesoqe} ideou, e| 9p euewio6-oouey (eouel4 ‘seed .Saulewny seIpel je jediouud |ruoine. JeOseW9) NUN Je WNjOA nud O66L 8 o1en \g09P uNynsah “aes ojopuey6 1wiod) ye UL oYod spur] Hey no gunaidu "6O6) ul “aide: ‘aGojosruin uy ayeuwos inguwuoo inne & (es6L-r ‘lolwnoquieg Inie4y9 ed “Seqeg 4m uy ‘néeunong | Sogeg ep ye10 ejewvewuodxs eUIOIPEW OP IMNSU| Inwud uy esayeo jndeou ne-S “a1o niseUEIY Nosed ‘NOSeULeW “4D yperoy @1e0 anu ‘o[esianlUN 1S nSoURWOS rou ‘ouewn ‘yeo) eopsowop 109ds up ane ee esi “edoonue episdes :eojsjoud unSyeauy up 18 NOY Nes NYV HWoUeE ‘ou ‘unsyp eumagaeays0 erehaUo}e eInOqEd "Nes TLOUA HOTRINSNAIA VIDO1OIOW a Tsran axisep feeioue YIVOIGSW SISO TOSNIA 9118 VIRUSOLOGIE MEDICALA 3. bun, 4: iitat, ‘5, improbabl ©. Spocia animal “1 fir sensibt 2. au cova sor 4, ou congtinfs $i 5, inielgente (primate, camivore, cetacee). ©. Suterinja arimalulul in experiment: 1. deloc, (moluste) tate (posi, arti), 2. minima, 3. modorat, G. Numar de animale: Dogma necontestata in trecut “humans come first” de 0 atitudine mai generoasa fafa de tot ce este viu in simplu instrument de cercetare si Albert Schweitzer) “sd evite suferinfa oricénd ale de laborator ram&n indis- cS wun, pentru unor medicamente sau vaccinuri. Cercetarea stin- izarea acestui sistem, producand animalele “germ inile consanguinizate, soarecii transgenici etc. Standardizarea Generali despre vrwsurl 19 embrionar pentru cultivarea virusurilor. Acest sistem tru foarte multe famili virale, pentru cd sus este net superioara lelor tinere sau adul late pe diverse cai si, in functie de organul lui poate varia inte 5-14 zile de la debutul embrionari. Din ce in ce mai pujin folosite in izolarea virusurlor, oudle de gain embrio- nate si-au pastrat important in prepararea unor vaccinuri pal). Culturile de celule au fost introduse In virusologie in 1949, de Enders, Weller si Robbins, care au primit Premiul Nobel pentru cub tivarea virusurlor poliomielitice in vitro, in celule nonneuronale si per tru evidentierea leziunilor histologice consecutive. Trebuie_mentionat 4, mulfi ani inainte, Constantin Levaditi reugise acelasi luctu pe explant de fesut nervos de la maimuje. De atunci, culturle de celule au ramas sistemul virus gazda predilect in virusologia clinic& si in cerceiare. Tipurile de culturl folosite sunt: culturile primare, linile celu- fare . Lor li se adauga uneori culturle de organ si icdrile histologice determinate de replicarea Virala in culturi de celule definese efectul citopatic (ecp). METODE CANTITATIVE DE EVALUARE A INFECTIVITATI Studiul virusurilor depinde de practicarea unor metode repro- duetibile de cuanti Numarul_virionilor nivelul multiplicdri ‘Aprecierea se face prin tesie cantitative sau quantale tabelul 1.1). In testele cantitative (de exemplu, formarea Dulbecco) unui focar infectant 1i corespunde, de regula, testele quantale nu se inregistreazé numeric parti prezenfa sau absenfa lor lao anumita dilutie. Ca urmare, se exprima tn urma unor prelucréristatstice tn funcjie de succe- siunea si rata dilutlor, de numarul de animale sau tuburi de cultura inoculate in fiecare dilufle etc.uns ‘eswojded ‘nyoedso: ‘esowosdes oyunu eojajoid sjunjonag ‘ouiqndessns ejewiue Jgns Joun © woujeurs eouelqwese ad pzeezeq as iodojoaue | | 1UeIMo0u! jnze UL euEUIN eIe0q sonpoide: ye}0ZI (edojaaue 18 episdeo) eojjoid unsyanuy i nonpoidey epzeB WysIS UN-RUL Y}OZ, erngea | @p Jeleiod (NaW nes Ney) WoUEB uIp eyMpoIe juNs ejunsruIA, ezoquis uy ayuesoroyul fsonpe son avo “ZeB4 UL “Yoo, ap asndoid aeinsod soja1eO}BUIN HAVEISTES eUINL eJeGo1d aIse eIeoq 1S EIB eMf9OIU axIUIP EIEzneO eTeIOY H9OM IN1 3TaLVINLSOd 8S 89 Baad aSQ “awesGoId Jojdoid © sued “unyos ep juoiezyeas nUad adeo|fy aqua!oyo I lp jnun wZeoau euNU SAE e NU BINNUOAe EISEde ‘!SMjo! “9922 pe ove sunque owas wozoxd UL pupEKO “ionene og ears Ne djewes6o1d sovenn innuobewieg’e ojep 9p eaued. ezolejery nes nd) lad 9 anno pn poncho oars 8 sndoid news an ]OPE UotewesBoud iso) ne sojare9} une ago ad de oto nop ned ud od ergo 0 a? an JO|UNSMIA yo}eOs> ‘ejuazeid aun e ‘ay!Gunjaid ofuaye| foun ‘000-000 1/4 Inzeo UJ aJeW IW eyse JOJUNSTUIA e eveBedoud esue$ g9 suansuco oo 0 '0 cons SQ} Ne eoReWO;UI UL UNSMUIA {WO}eWUAr adeosns jfoaigns 0009 joun esd ul sei raifoqyut earenjadied yuued exes ajueye| aji +o+0 S00. -2ajul uy nepaco.d sSejeoe ezeozn 9) ja) e1Bajeng “ues09 eee eer 35 00 ed ra1ep waiesye no eepo ‘ojabuejaysIW in| © cuoySeu ep eniz ul pou sees ‘awonyuoo ele 09} UN BYE NU prey UL InjnsmUIA ediiod BBIeNUAUOD EIUeSELOIU 9153 (400) ereniend erouns3 | (alee) earenven ewan 8 UL PupoYAR) s\EIDe}U UNOs|p AddOY LYLIALOBINI ¥ SIWANYND 1S 3ALVALLNYO WIVELL VauVEVENOS Ut gidwigju) 2s 09 e980 no + mae WwojWSUeN inWSUEdayY “ou96 faircis ies InoHed JezayUls InsojO} UL f-NPUBWIN|Ep Je}Nje0 jNUSH no pupdosut uinyp ‘ebueIs e1 9p) OUSA ela 2d So}EN SUA AP oles EL “Bly jwigns |e34 lun oueo uy pow iSejaoe ul sajndwoo joudwoo sojareoyeino|e9 a|unsnulA ninugsjao_e ai9j6eu ap eniz ‘ae 9 e| ‘ue aseoay 9180 afuede imseo e ‘ojaBuEjayoIyy nyt 4ojeseo}einoye BaLUN} UL SnUIA Op |nU “ouojeyeW! Sues UJ JeWNU e}eo|de AISA smuIN Op ejeyONA e129 UI isi 18 Bze90s0 sep ‘o| omed *\no 24) Uy “0189 Ut jJ0q UL esnpe ys0j ne eqoid ap jeyisy “ejeUIA eiBojoNS nyued soyioads agoid e0 ayejde0oe yuns oes 9/2 stuouGey oun © NES [eJIA INjnwOUDD & sel}UOpINE ep eU1ePOW YBOJOUYL “ejeIIA eIBO|O ‘2 opnIOxE NU 80 Besd ‘eyGISOdu! Nes ajeoal6 91S 40) 021 unzea ‘uy “@JBq0:0 y Jod aesaprzep ese Seq Instuin Bze9jOzIE1 8s enBUIOg AfjeWiUe B| Og “y 1z unsnan exdsop feyeiouey a VIVOIGIN FSOIOSNSIA 42 VIRUSOLOGIE MEDICALA darizate in inveliguri continue dupa regulile simetriei ioosaedrice sau helicoidale. ‘Genomul este purtaton determina antigenicitatea virusurilor. viz virale; capsida sau anvelopa BIBLIOGRAFIE ional naming of viruses - a digest of recent developments. Arch. Virol 7 Gann AJ. Principles of Molecular Virology. Academic Press, 1999. Harrison ‘SC. Prindples of virus structure, In Fiel’s Virology. Raven Press, New York, 2003, p. 37-61 Mahy BW. 'A ditionary of virology, 3° ed. Academic Press, London, 2001, T CAPITOLUL 2 TAXONOMIE VIRALA De retinut: Taxonomia virala actual’ desparte ribovirusurile (genom ARN) de dezoxiribovirusuri (genom ADN). In aceste regnuri, virusurile se grupeaza (de la simpiu la complex) in tulpini, speci, genuri, sub- famili, familii si ordine, dupa crteriul inrudiri in’ secventa_nucleo- tidelor din genom. Cr ragmatice in taxonomie (dupa calea etc.) sunt azi Taxoni Pentru clasificarea tuturor virusurilor, ur familie, ordin, gen (tip) sunt bine conturate. Del face in functie de proprietatile virionului: morfologie, proprietaii fizico- chimice, compozitie (acid nucleic, proteine, lipide, carbohidraji), orga nizarea genomului si strategia replicativa, antigenitate. Unitajile taxo- privind depozitarea jenitatea gi mai multe proprietJeo1pous Je} yewNU eLBUINUE ION j9qe) 8 1Z Injeqe) wo nquad eiapen ep jound up ejueyodu z eueBoied uns 4z aleo up ‘unsnuin ap mjwey [9 aiSeounda! ALDI ‘quezeid uj “eoIpaui 919p9A ap youd up gueyodu jwes 20 ot U) RIEWNdKS JA Nay © pie 910 eoFEINAID “erEpIE=yOy oWaUNS - H ‘eoUPIESOD! guIEWIS ~ >| ‘VaRaaY esq] 2] oy zal ‘oLae] —eapuvaney] oz i J 1] uf opti oxpvoney| seu 4 e | ‘ozo aepunonwouno| y 9 al a a mai s| of al oes cepunevar| wa y eal cors/| —eepunevarcg| za zt 0 ecpuvcon sveel | ose) sepwrapqe A oess| — sepunesung| | coca) oxpannet| Ee 01-03] eepureto,| 2| ore] senunoneo| $2 i oe-zz|_eepunewoard yeoypo0] wows ‘2u9}014} erena.q0u| apse Jeuny| — eyenoi9|_evjou emues} Yivorcaw allvousinwas no RinsMeiAoaid STITEIONIE re wmsevi (:210 oyeBawowo ‘so;o ogni jnsnun ‘njdwexe) jeyj-owss}eW ‘jeoN esIWSUEN UNSKIA (euaB0ye) J9x0) epodome ep esiusuEd \dwaxe) ebues uud osiusue: unsruy, ‘njdwaxe) eueyee a:ayusuey no - ‘njdwiexe) greso-1e09 ai isuen no - "- Hop jod 106 9180 ojoxzoiguisf| “Jen o1Go}ONO UeBE e 10 8p e9Ie9 N19} “HO o1UN ydeup eiSes0|0; Ue!IUID nAUed EIN eyEO} aledytseIo 0 YOISOTOINAdIda JYVIISISVID RoR, | j -woypan seInj2 lwsidon ‘epze6 op nujsods ‘aiBoja1es :oo/60j019 otlejoudosd “9 rzjoeoulue ep elusrces ‘aifouns ‘pienogjow eyene16 seUNU :2jeIA sojoUIB}O:d oYfeyOUdosg “¢ ‘@pyoojonu ‘9p eluarses “sjuawBes op jnipwnu “eojeqejod nes osouosuEN op Insues ‘(9 ‘7) sejnowo nes seeUl| (spyss = Jejeuds nqnp nes njduys) auds 9p jtuguinu ‘oI9NU poe 9p Indy :InjRWOUDE elferoUdoug “2 vedojanue efuezoid ‘oujows “"guuoy ‘a1fe) anjnuoUA oyfeeudord “1 areouisto ny, -tuod juoyuyop wey.0 ejreojgUUN ezeazIyN ejeMoe eIWOUOXe (edojanue ee) ayes yu 18 (RnHeBaU ajEWEIod no SsNRYY WOUDS no) ejesIMEGoUOUOU! JO eNlOp. aynosounda1 jso} ne (96G} ‘wHHesnia|) a\BojOsnuIA jeuoijewiaju] jnsesGuog e7] “weolde: e euNWos si6eieas no jwey ezeedn6 (S49 31WOUOXE} dm6 nou un 9180 ida eiBayens 1S eojWousd 99 Baa9 UL auNWOD arsjDEIeO smu idwoxe ‘sua ysuayoee no = sRuAqoyY no 18 aunwoo STA 9p tuidim uIp eyMRSUOD eUfnW oO guzesda: - Fads ~ ‘201uouoxe} §woBaje9 ajaeojeun wiuyep ‘xejdwco e| njdwis e| ap puNLIog ‘ouoyo nes a1e{071 ‘judy “undruBores yoads re1g99y upeD us Emap eaInd JOA 95 pow 3s998 UI “aads o1eD9y e} BIIeIOP WOR 9} B19 9d 0160, YIVOIGIMT SISO TOSNUIA veVIRUSOLOGIE MEDICALA RIBOVIRUSURI (fig. 2.1 si 2.2) 1. Picomaviridae grupeaza virusuri fra anvelopa, cu_simetrie | hepatitei A) desi variaza ca dimensiune intro 7,2 june lunga (0,6-1,2 kb), noncodanta, la capatul 5° al portant pentru virulenta si pentru replicare; = 0 fegiune scurta (50-100 de nucleotide), noncodanta, la capa: tul 3, necesara pentru sinteza spirei negative complementare (unde se atageaza aga numitul semnal de poliadenilar codificd o singura proteind, livata ulterior in aes ‘Arenaviridae (S, ambi) Picornavirdae (N+) Coronaviridae (NS+) RNA viruses Positive strand(+) = — ‘Sssegmented NSenon-segmented = 100nm Tibi pat andp- Calciviridae (NS+) Fig. 21. Imagini la microscog nibovieusuri cu polantate poz ‘Gono segmental s1 cu polartate fe | | 1 Texonomie viral 20 Paramyxovindae (NS) Rhabdoviridae (NS-) Onthomyxouridse (8) “= _RNA viruses Negative stand) | | and Double strand (ds) ‘Sseogmarted Semon sogmartes Filoviridae (NS) int&aceleasi caractere ca_picomavirusuri iei mai mari (35-40 nm). Exemy lor umane gi patogeni asemanaitori fa porci, cain m afecteaza in special copii sis i. Alte virusuri ARN au fost acuta (BDA): astrovirusuri, coronavirusuri_ $i rotunde, neciasificate: agentul Norwal Togaviridae cuprinde virusurianvelopate, 4, dimensiuni 60-70 nm, genom ss cu pol spectru larg de gazda (primate, Toga, flavi- si bunyaviridele al arbovirusurilor (artropode’ bore viruses). Familia togaviridae cuprinde 4 genur = Alphavirus (virusurile encefalitelor ecvine de Est, Vest,“eone -oidurise ‘owasisied poo oun je fuoGe - seuumewnds “VAIS 1e o16ojo0 jmueBe - AIH insran (§ ONS ele entesouebep ue) junfooje soun ‘tn #8 | sosi esnjoul 150) ne ames gseade UL “euunw | Ney ousBo9u0 ejunsruin | 8q “O18 oUIAOG ‘esd pads - aeuuinoaUQ lwejans ies), EZEONIIES “9IUEUIOP sO}a}DO;WY BaLeAYOR Pugnowoid ‘eveo (unsnain ‘aueBqUE ‘iueBoNW) jUseIXe UO!eJCO JOUN eyjuansayuy 2] gud sjUsj2} ougWE! od ojuNsruunosja: (jeuIKOId ONGV) ByesBo}U! 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Parvoviridae sunt cele mai mici virusuri ADN care infecteazi ‘omul (18:26 nm), neanvelopate, cu genom ss, confinand spira poz tiva sau negativa in virioni separafi, Doud genuri paraziteaz’ ant malele homeoterme de la paséri la om: parvovirus si dependovirus, Al doilea gen ilustreaza categoria particulara a virusurilor defective care reclama coinfecjia cu un virus helper (in acest caz, adenovirus sau herpesvirus) pentru o replicare productiva. La om, acesti agenti au fost ‘anemile drepanocitare ca urmare a sav"homalogens “si in. “bala ‘a ba Dependovirusurile par a inhiba oncogenitatea “experiments 8 Virusurilor herpetice i adenovirusuril 2. Papovavirid icosaedrica, cu diamet gazde distanjate filogen etaii oncogene. Doua subfar Polyomavirinae ~ nut icnd capacitatea acestor virusuri de a determina tumori cu localizari multiple = Papillomavirinae - cuprinzdnd agenfii verucilor sau papiloametor cutanate sau mucoase. Papilomavirusurile umane sunt legate de dezvoltarea carcinomului de col uterin gi a altor neopiazii intraepiteliale. 3. Adenoviridae cuprinde vechiul grup al agenfilor cu tropism adenofaringoconjunctival (APC), respectiv 46 de serotipuri care deter mina afeciiuni acute epidemice respiratorii, digestive, conjunctivale etc. Sunt virusuri neanvelopate, cu simetrie icosaedrica, diametrul 65-80 I prezints Taxonomie viral 31 genom ds circularizat_pr intermediul unor proteine legate ii ADN la cukariote, transportul nsformarea celulara etc. 'Poxviridae| _Herpesviridae DNA Viruses —— 100 nanometers viridae cuprind virusuri_ he ism exclusiv pentru hepato« au genomul partial ds, aproape circul leva aspecte :za_materialului proteic al anvelopei si ‘genom: = mecanism neobignuit de replicare, care include reverstran- serierea unui ARN viral mai mare decal oel genomic utilizand o virus. codificata: de gazd ism limitat la hepatocite; persistente cu productie continua (ani de cu retrovirusurile, avand nu si omologii in ' secvenjeleB¥8-Pre'ser:9002 1m yndod FBI © Ul suoYDe.aIM axnerodo09 YErom sIsavEdoWed SAURUD.OR A Sepedsiseno) °y oU;pUY “3 UOLOUIED “pr pow alavusoraia (ise) gwew © 9p) reoron aswusuey 1§ yo}oen uud esiwsuey ‘oBugs Ud fa mn fenioe oaysin ireasa out nen (Ruane rived e2eeido. eaiojauopde voleayseio, (esoumue) ea -eGau nes (WNYy Bo a)Sanas i$ sofsqul ajsa) eagizod ae] at eyeod ssNay “nu nes jeuewbes ‘ejNouD nes seaUl) te Bien TOTOREL nes nidwis y a1eod yen d19}0NU INpioy “ejeque nu 4ep “(uNsMuIAOG suixozep) NAV ay “(unsnugu) Ney ey ulluco ajunsnuiA “Jeo 4sejo ngjued ejeljuase yuns Iyeo|idos eiBoens 18 njnwoUed idoig “@uipso ‘yiwey ‘unuab ‘yoeds -uoBoye9 ejeseo}eWN IEA eIWUOUOXe} *xa}duOD 2 njdwIS e| BP PUlUdod bz0WuIs wanysued, Indrub up fuaBe you y§ wnoaid eyep reynedey “oineu suonoeju! o]uc.49, nyued) SMA YNIHO nub |niyoen nes id) euuoyuods enoeqns somnedojejoous tijue6e weuoluow ulais's awalqid Bzeaa!I ajewJosepeu so|WOUeB in ffuoBe 1ou ap BUCS eailadoosaq LLvoldIsv10aN LLNaOV (wins youn, soun 1e 18 (euio9E 1d BoMIpoD aue9 WN UN nunduun eusseidoyo UL Boiidos ‘fedojanue iWoylA no “(wi ose-00z ew Jew) efe0 puudna eepUIAxod °9 onsua}oe1e9 a12INj99 pas UL laluate) eluances) ~ ‘prooyo oedoyo 199}9 - tnajonu uy eavejquese i$ eoVe ‘yrayan oqejow U, ajeoydw awizua ep aiew sewnu jnun ea: seaiBojoig fzjeudod % unuoo ne ajunsnansed injnwico1es yerp0se 8 (HH) weg: ‘y AHH) 19% wn (e sruasadiey uewny ~ un (ZS L_-ASH) Z #1 xo\duys sodioy jnsrun 1od aqueyodwi yuns ydo ‘aune}oowoy 1S joz1 unsrulasadiay Op QOL 21S@d e199 UIC azad ez 18 OZ} UL auijudd oJe9) injnWOUeS jes0ap 2) Jaysave 1 uquiew wives Onu “I ‘euoulosdeo op Z9L Nd ‘goupaRsoo! aise episdeo ena\ oE-oz1 sNqeueA eyse ingoweIg ‘aueyuauuns arep/sdeoued faye edojoxue no ‘axaidwoo unsnuin ezeedniB oepunsodioH “S VIVOIGIN SIOOTOSNYIA 2| | CAPITOLUL 3 REPLICAREA VIRUSURILOR De refinut: nul reprezinta forma inerta a virus faza de platou (maturare, asam- tivirale specifice pentru fiecare etapa a CICLUL REPLICATIV VIRAL Ciclul_replicativ viral a fost elucidat desfagurarea_evenimentelor unui raport virusi li de infectie mari (raport putem pida a celulei gazda prin Numeroasele particule virale ads membranei celulare (lysis from without) de virioni cu genom defectiv, rezultind Curba de crestere de o gen de crestere linear’ si de platou.40] eareidno eve uy esnsew Uy yeuo/founy yUNS 18 (YICOUN * ellqospe ieunu ezeipew - (uojdaceios) eyenuye eseof s0}08) tyMaNS reuneprdo - J93,,10198) ymauB ISEIQOXRY - 404, anSTIADSY ‘Eiuerba) 2.493. med) TEWWOL Sunzope a] [e5e9 HD uDGnue Aaued| 94 navel 109-1885 DED) wawordusoo naved| ager msnap| nooo nawod| sau 0342034) RINSNYIA YOLMWANY IOLsIDads IO1dI93u 3G FTAWaxa re anagyL (eS arepisdesap “erezyour ueoyipou inun eifouny 1S eumonas ezeowius 1S 4 2] 1eidepe es insnun eo Je 9183 -q ~0}sue eanowWOld 960 JeuWEs UN gUIUNIaIaP BIR|O ap ininsnuiA In IEW “e}oIsa0e euEiqusW ep WU OS ep ElueIsIP o e| 9p 1eSe}e Wa} 9IS9 IMsnuIA “PED injmuBWe;duI0D e ajuaL juewbey nun eaiejdn> nyuad 1S eyonios 1S ease aIs3 “g - ozzioge 46 - ‘njdwaxe “aq, “HepOW_O tuoideoos) eyuunue op s0\9INI90 eluEysize1 goydxe so[o\de0Da1 est -deoas soun efuazaid ap ejeuolypuos aso gu9} eilquospe ‘iSMo) “UB -oxe snaBraue |nyode ep 1S ginjeeduie, ep yuepuedepul aise Insa001q gueumorg ee1eDSW UIP aeyNZa! BIMja> - UOWIA JUNIZIjOo eareWIN 8182 epzeb Jainjeo eueiquaw e soUOUIA ealesery “ellqospy Bareiagi}o 6 weLequese ‘eeeiMeU :noeld op Eze) - Yeyeanjonys) enipsey s0joutojoud ezojuis 18 jeluaied injnwouab elujew ad juaBord sojnuioU® easeui9s -uey ‘jundwiy s0j@u\ejoid ezo|UIs eeou a19jS010 ep ez) - ‘eavepisdeoap 1§ ealezqeuiaqul “ellqiospe :esdyoe ep Eze; - odey ten Eze} eve0 Corepeeaso -fose4d uopenety) eaunrboy ez) - * ‘gjozes no podes uy san op esfonpold <——— om —_ rey *yuoneumew 100 i" eoons, ud "epze6 ein|@0 Up ued je yoodse 1S eleinp eorewin nu 1S up ensaoe e9 Ae ZED 800 p affouny ul ew eo e aquauodwos tied up pzealoGns uejnjaseai uy "epze6 ginjoo - snain “Sip ged 0 aie iS Jen Sroibon op wzes ‘ayeyayep y jod nu wh mean ‘aie Ul jens! un isa 1S aifoajul ednp yepew! anuKY ep Oz-OF te “Toqinstian warmndaRy YIVOIGIN FIOOTOSNYIA OF38 VIRUSOLOGIE MEDICALA of viropexie endocitoza, cum carea EBV inca In acest la pH acid pentru cor penetreaza fie prin fi ‘complexe anvelopate Este cazul retro, paramixo, her- doua mecanisme dis jembrana celular sau (2) | | | | | | Ropiicarea viusunitor 39 plex poate si-si fuzioneze anvelopa la nivelul membranei celulare sau 58 fie inilial pinocitat si sa realizeze fuziunea dupa endocitoza in pinosom, re independent de pH. Decapsidarea. Semnifica separarea fizicd a acidului nucleic Cele trei etape: adsorb- jerderea pasagera a infec- ca faza de eclipsa ear, care include urmatoarele Sinteza proteinelor timpurii nonstructurale care participa la pro- sau a polimerazelor furnizate de celule dive structurale prin traducerea ARNm din ‘in primul rand, componente enzimaticé sau pot participa carea viral. Durata fazei de crestere este limitat de capacitatea ulare. Infectia gazda deter- Faza finala a ciclulul infectios este reprezentata de eliberarea lor progeni. In cazul lor neanvelopate si al poxvirusurilor Colulele infectate se dezagrega eliderand rapid viionii nou sintetizaf in cazul virusuflor anvelopate aceasta faz8 confine mai multe etape: = maturarea componentelor virionale; = asamblarea lor la nivolul membranei celulare sau a mem branelor care marginesc vacuolele intracitoplasmatice; = eliberarea prin inmugurire sau liza colulara a viionilor pro-‘918 Bzejduosuensiones 1S jeilied Je|noHD In) ~nuioueS & ouGequ, ep ewizue ufjuoo aie “ajunsnimeupedoy - ‘unsrunouape nes -sadsoy 9p syeysise Yewinu golides as A129 ‘enyoojap sjnsnuinonied - Nyduisxe op eo "yehyos oveoydes ap musiueoow e} ap sjuesarajul fdooxe 1$ oufuoa NaY JolunsruA je aueu ndnigy twoBoid wuoun ezeajquiese 8s o1e9 ul) ajeunjonys sjouiroid ezeaziuiny Inuinn Yewny oe UIP unjoID aynu few uj BIeOSeYSBP os easoUDS uel} 4B! ‘soffoejul 2188 esA NY “sleWUN 2 “Wey e1oUdb Se na ued lapze6 ‘o/@ siouosueN ep ofewizua ezynn od IS (JoLNsnuIAXod erldeoxe no) najonu uy eoydes 8s NGY WOUD6 no iunsniin ‘aleluetua|dwoo Jo;euds ezejUls nijued eSenses e120 |S soIWOUaB ofa) -vowiBexy e120) ezeadnub e1e> sosinvaid un-nu) yeIQuIese 9150 - ‘oJeuA oUlsIOId UL snpen aise - wleunsep enop a1e Bie9 WNYY EZeaZnaIUIS 9 giuiew giseace eq eeUi6Es SPAY wOUEB ne alunsnunoON, ‘woyei6e1 18 gjemponu}s soj@uIaIO1d sojuOs unosid ezawuis e} ejSanies aio eerfied owibun] no WINey ees0L08 wen nujued 1S geqo|6 awiBUN} no oWWoUR Nyy eoVeuDsUEN nijUEd aiSemes jeiGeu) mjuawiBel4 "epzeB Jejnjao |nwoue ul ezeoI 88 jeunoid spNaY “(ONGY) suOsUENSIoNe jeuAod NOY ezaIUIS my) ued eliqew :alfouny einBuys 0 no wiouaB uN ne sjunsnunosoy, WN 2 euorfoe od “ere\ueweldul0o ‘eanizod ea 1S ye0 “poRUoUED "eA -ebau exids 1gIe ale UL “suDsiqwe [euOjfoun) 16 jeWoWBed}I WoUdE Ro iojunsnuwedung nzeo 9350 dub 1509e U1 BIqEIOU aifdaoxe O “210 ‘nut e1oyp uaboid Nayy nujued elLeU ydoup INOS eA O16 (+) NEV 1S Way ‘MOUS NuW Kejee ad oleznatus ep ‘jexopeiey alu! -oue Nay 2 auniBai iSeae0e ad ep aulejoid soy iw eovoUDs -uen juad aueo aienyo ep seus ajdyinw oulluco WNW (é) IS quE}AIUIOU eso UOUIA UID SeAXe NW (2) 'ezeIdLOSUEN 0 UifuoD uo oun (1) cunsnuin 9qse0e rujued woWUyEp sjUdWIo}o oN Jede ‘eseULIN 29 ‘(uafoid Nuv ezolUIs) ennebou rouds ezajuIs mujuad aanizod ouejeweldwoo feuds eeseuosuen nijuad elujeu eo aisocons o}Senios woueB iSejeoe po 9189 99 njued onsusjoRIeD (ole:neBUOUOW Inupio) enjeBeu eyewelod no ssNuY Jo|unsmuiA jndni6 osoIn} “2018 alunsnunopqew 18 -euave “-eAung “oxwesed “-oxIWoULO sjeinjonas sjousjold nqued WINYY pugwezada: jel snpenou njnwoueb eawibun| no “ueBoid ynuoues puejuozeides wousb InjnBanu) eoubuny n> + ownue 1§ (+) NeW 8p aIuaIp toads nyued efujew jdaup arenes e129 piequewe|dwoo gids o-yu! nwWOUe® Bou! lode nNOSUEN aje79a, -uls_ 9joUlo}o44 “fell esnpeN B/S | e auNIfiod o lewnU ED mde Wud sojunsruinewiosid |e [20 9p BxO\ID Jo|uNsnuIneBoI nWoUED Soa nanumen nannies teoaiee rd usu in ones susan somssmaesonUeneSNOSEEES Tons aaRO | (+) sexy sojueboxd ezauis nsuad jo ynpue e} “eluew ase a2e9 any Bau sieluauiayduoo jauds ezas nquad glujew eo aysonwes zZ 1S TeA “IP 8188 JOUeIIN eed DHe}O/dyod Josunoeid InUN ezaqUIS naUed WNYW 29 aigewies Jeuojounjiq }so sojunsnuineuCaId nous “unsnuinsodioy ‘nidwexo ~ NOY Unsnuin “IA “unsnutnoos 'njduioxe ~ spNety unsnutn “A “Dnsnun ono1 = areussuensiones uud eoiide! 8s 6169 ssNesy Uns “Al “oy unsra 4aoxiuesed 1 oyyo - eageBeu eyewejod no ssnyy uNsnuiA “unsnuine6o) ‘niduiaxe = reuoifouny ewoyp ‘eolwouaB junitiod no engizod ajejuejod no ssyyy uNsTIA “insnuinewscoid “njdwoxo - ennizod syetuejod no sshvuV Unsnin ‘sep ose uy 2:0p0A 9p jound up weds 98 sjuNsnuA ‘aroUIN}eR NO pIode Sojouinin. ezeiu's e0se=loqe 2s nes aieinjeo sojoujsjoid jazouls eidase ofejueAe avejuo0 a] eS ‘180 ongjeoydes yBojes19 evjonzop eS Ingen ejunsnin “ou ul -dleuIA nes exeinje0 ezesjeid ap leno Joven ye FzeoWN e1e> uOSMoAld oun ezojuls nes giein guigjoxd o1ed0y nuad sjevedes WNUY OP toads ep ezojuls eundus| 29 e000 “eoluogsioouoW alesou rewnu onp -B]) ajajoueyna ‘eauawase aq WNYY |euy ul eseue6 e nuqued ewiz “vo iticosd ozazmowls I6-es oInqaN, unsnuin ojAU! feu! 2j00 “MICWEKS eq ‘ede: eweod es es NOV 280 18 129 ‘Ney SluNsniA ig]e eo nijued “sjepnjo inqan uoBupr|su0D aywnuy “sjoLENNA saynje0.tidold olojaid ezoiUis op ejowsives0W op osnpel IS eIeye v9 s\NOsOUNDD! Ny ep sPeds epzeB jeInyeo eyUIZaxd ES angan ;NSMAIA ‘nyMWOUEB savectuedi0. 9p yv9i0\4) “OpesIA 4ojoURB foIsasdxe eiGayeNS seal 4] ae g A oneal re a ‘cusp x 2) ue fone) eve evel] tata weal ye uy Suvoral IW 30 Aiolo InTnoaUUNI V IS ySdIT93 30 IBZ V YALWIXOUAY vivUNG we W7vL Ire inreqe) jeuen 9Is9 reoyjdar ap injnyoro Being ‘ayedojenueau JojunsnuIn Inzvo UL yeo9p suAAUI “TaINJoo JeIDOse IMINSNIIA e eed ed soaNU! Je|nj@oeIIXe SMA |p eayeyyUED ‘ojedojenue JoynsruA jnzed Ul nui ep offouny ue VIVIAN FSOIOSNYIA oP42 VIRUSOLOGIE MEDICALA virusurilor din celula infectata. Faza finala je este uneori complicata de sinteza dis- Jor genomice si proteice. Consecintele pot a ‘88 determine infecti ca sd nu mentionam prin citl2a (picor ‘ambiare ta nlvelul_membranei celulare si eliberare prin | virusurilor ARNss cu polaritate negativa si al ‘este semnificaliva includerea in particu- (cate de gazda (in special din a) care pol fi relevante imunologic. eplicativ sia strategillor de multplicare gi pism foarte selectiv pentru celule inalt specializate, HIV focitul T helper sau virusul herpes 6 pentr B, sugereazd cd noi strategii pot fi imaginate si ca virusurilor animale sau chiar Umane nu este inca incheiat. BIBLIOGRAFIE Baltimore 0. The expression of animal vius genomes. Bacteriol. Rev. 1971;95:235- ite JM, Littman DR. Viral receptors of the immunoglobulin superfamily, Cell 1989°56:725-726, CAPITOLUL 4 GENETICA VIRUSURILOR ANIMALE De retinut: Virusurile sunt segmente incapsidate de material genomic (ARN ‘sau ADN). Variabilitatea este © propr care rezulté din mutal Frecventa mut mare la virusurile ARN (10) decat la cele ADN (10° cabil prin absenta mecanismelor de corec} “proof reading mechanisms", in cazul polimerazelor ARN, TIPURI DE MUTANTE VIRALE Structural, sunt doua categorii majore de mutafi = punctiforme - urmare 2 schimbarii unei baze din codon; in deletie - in care transcrierea omite sau “sate” un seg- pe care genomul progen se sinielizeaza, Functional, mutajile sunt foarte diverse. lata cAleva exemple + mutatii condifional letale, care se mutipica numai in anu- i selective, De exemplu, mutante reci, care se replica emperatura suboplimald de 32°C, sau mutante calde, care se replica la temperatura supraoptimaia de 39°C si nu la cea 4 pentru mamifere (37°C). O altd clas de mutali condi este reprezentata de multantele dependenie de gazda care se in celulele unei anumite speci le condijional letale dependente de gazda au fost stu- diate intens in sistemul bacteriofag-bacterie. De regulé, ele sunt urmarea inlocuiri) unui codon care specifica un aminoacid cu un codon stop UAG, UAA, UGA, codon caro telizat. Adesea, proteina “truncata” este nefunctionala. In funch codonul stop introdus mutantele se numesc amber-UAG: oc! pal. Alte mutante virale funclionale cu aplicalie prac 51 bioinginerie. sunt = mutantele cu dimensiuni ale plajelor mai mici sau mai mari decat cele uzuale;‘o\dhINW eUs\UedOW Ud aede eISIAREY “elus|NA op ‘uej9e189 IpuEgopa: jod UINSeA UL asnjoul aJenUEIe ouEINUI ‘njdwoxd up In9UeBuOU asa wowouey ewin up pow Joun efupssuod 4 aieod nes “oneqes indjous) e| eissonos euUiolep a1e0 ‘exepundes jens Joun |neiinze1 y e1eod quermu ymyndyousy ersesdng mnWuod o}d698) J0UN efua}sIxa oundnsesd Ebeo}o.}9y elusioLsTU sei ‘enIo=Jap jUALLaIU) BjnOIed no lo1fo9) uloo eoseuun ase BeojoWo eluaiapaqu) “eBeojo.o}04 nes eBed|owo y ateod lusjsizes insues u) ‘efuoseponu, soluoues ueowpow eNSIGaIU 9s e EIR) “ye|UaTed uqwE EI 9p puluanosd aulsjoid episdes uy ezeoqo\6u e129 woG0.d eyinze: 8120 up ejxlu) wooiut oun ewn uy exede ajdouey snaarsowy ajeain ieifeyndod eo. -xejdulod_@ einqujues sa00sd yso9y “uoUIA snBUIS UN-stUL sOIWOUSB doo soynu) jew eoresodioou up eynzar nwspobizos0}0H JUeIMU \nIndqoUD) wrsaidns 1 elusioyoqul ‘oidjous) inooIsoule” “MUSA -OB1Z019}94 -weuolluew es|s80e anu) “eoiuOUEs LedYIpoW 4oUN inIe} -inze uns nu @1e9 ‘yeIUELEd ap 2} u09 syUOUOMLUCD ued “unsn. 1uOUIN ae euequiese ‘anu! aojeue6uou runioes9juy ezipuqiy uud nes aijoujsor ap owieua no injnuioueB ealenyo HeyOseO! ud ‘weUIqWoD=! Ud einuilqo Fey ajeoygnd jso) ny ‘(e4iA JONWOUES Be jey oun eauNyjsUOD e gNfe GxeD sjUEUER 2p 6ue| napads inun exdnse ep jose eISIKy “UEUIGUOIA: #6 ufojOP ‘iniasans 9p ereuuersp ajeuin ojueueR iou esul eGnepe ajeuiaque JojajusWeo|paw! @ nes Jojebe;nW eoveZINN “euede ue|UOds aleInjeU OWUEINW eUIWOSIP eeod slewA sOW}eINdod e eoIdoUE) ezyeUY VAVIND ION VOLANIS ereyondyynu wud eseapoves ywinu 8-5 UaUIOUa) IS80y “oSMIq aySaiods eeTEHIANOOJUI 1 ininWOUEB ele ‘98iaAp 9uOz UL 1ez9| 1UOUIA asquL eexe1edoo9 eonpaid as (2) uud erenoeu) ejnoped ap uw 3p ans puguifuco ejnooul) ello pew feoqdninu ey Y8MO), 1d @Zeq alju! aUa|eA0D mye6o) 2p 1o9Ju!) eajeoiides eajeyoedeo ezeany eI | LNSMUIA JO}sage & ojeIOIReNIN NO ealOIpes| “JE/eIIdS nIaND NOW nes NYY wloUeB no 4 90 B| NU Jep ‘eoIBojoIZy eimesod -ule} @| 980.9 e120 lUeBOId pup ‘sodi9a1 ezeaeidns as InjnWOUAB w BieUnae ToRRRTTA Bones | | | | a je s}9u! -woxe jmoleWN op ens ‘2u0z UL UE!OYE UIP o}e|INzes Op\eo ayUEINWE enop :njd vauous} Un e1se eoseuoUTe/du0D ‘ven woue5| 20H nstwnoguxez00] ‘000 cous unsnsKogD 000 ou Unsrumeupedoy| 000 1] ‘unsnsinonats out RuNWONO vAZLYO V1 WLvLnW 3a vive We Wn7aaVL “ajedub ounsnuin :njdwexe ep ‘eo ‘yeluewbey woues no Jojnsrin Inzeo ul) aquarsixeaid solwous6 squatubey Joun eeleuoseal - ‘euejuawe\diios 2} eonpuca o}e0d e1e eolWoUeB junfyod JouN eeseUIquCDO! - ‘aonauad auaus “Juang oynW ew eyNzes jod wunifoeajU! a1se98 UIQ “eo}}eUa6 runifve siequt_uud rSnposd onuepisenb ye\uesed soun re izuqly yuns eyNzes iua6oud ‘@iewin 29 “jUArsay jUAUIIUAKE UN ajsa “DqUAPL nu JEP “Ie) luis WouD6 no 9[euA ojnomed oynu 1eW Nes ENop No ajnja9 ouNBUIS foun e eueynuis eVfoau) “unsnata aur eonauaB junioessyut zo0g| wo x 5] wg] 002 aor x 2 ‘000 mun sss ol 000 ‘ven oss ol ooze snl wayerBove® nuy| _ sproanu sewn] ‘ua sewn sn610] RUNWONSS VANOLYD ¥ YIvWULS3 YUNLONNLS re maavi, ry 18 ry greae ut eis 18 tunoedd “euwstuei0 sedwo0 PeunsuowG oneuw}2ue yoyep no ejeiueInal ~ jeanjue aqusweoipous une e| 2103}I201 “brenueye th. ojunuigoen ui ejezinn ejenuoye alezhe|uls jUNs injnwoues e enqeja! eae fayfe no Hodes ul ejeuia so|nWoUAb e eA VIVOIGIN JISOTOSNUIA oF46 VIRUSOLOGIE MEDICALA - reversia adevarata - sau refacerea mutaliei care a contribuit la modificarea fenotipului salbatic, = reversia compensatorie ~ prin mutati, secundare intragenice care corecteaza mutatile primare; © reversia extrageni¢a - prin mutalii compensatorii in alte gene le sau celulare - amestecul fenotipic si mascarea fenotipica sunt cazuri particu lare de complementare. In primul caz, dowd te (de exemplu, polio 1 si 3) Infecteaz’ aceeasi celula, rezultand capsida'‘mixt’, care conlin determinanti ai ambilor parental doilea caz, virusuri complet neinrudite infectesz& aceeasi celula, dand nagtere unor progeni in care genomul unuia este mascat in capsida cel vi PARTICULE INTERFERENT DEFECTIVE (PID) in 1952, von Magnus a observat ca pasaje succesive ale virusului gripal pe ‘oul de gaina embrionat, efectuate cu inocule concen- fe, determina, progresiv, scaderea de mii de ori a concentratiei jor, acest fenomen a fost explicat prin aparijia ivi care au utmatoarele proprietaj + conjin proteine capsidare norm: = conjin numai o parte a genomului standard, * se replica numai in condifile coinfectiei cu progenii care contin genomul integru (progenii standard), ‘Coinfeciia particule standard - PID conduce la trei fenomene: ~ imbogatirea treptata a stocului de virus cultivat in PID (in fapt, saricirea infectiviti, care este atribulul particulelor standard) ~ interferenja cu replicarea altor tulpini omoloage, = reproducerea mai prognanta a unor fenomene asociate infect Virale ca: inhibijia funcfilor celulei infectate si transformarea celulara Condiile care favorizeaz’ productia de PID sunt inoculele foarte sau aportul continuu in sistemul virus-gazda de celule infectate. PID contribuie la instalarea fenomenului de persistenta virala, la apariia unor mutante daletate sau la protejarea Feplicirii unor virusuri defective. In incercérile de izolere a virusurilor care reclama caleva pasaje oarbe se objine tocmai epurarea slocu- lui de virus de pariiculele defective. Premiul Nobel pentru Medicina din 2006, acordat geneticienilor ‘Andrew Fire gi Craig Milo, igi are originea in studile anilor "70 asupra PID. Cei doi au descoperit mecanismul interferentei ARN (RNAi) RNAi éste un fenomen comun la piante si animale prin care se ast gura reglarea expresiei unor gene datorité.inhibitici specifice care fezulta din formarea unui ARNds din ARN mesager si ARN interfe- i | Genetica virusunior animale a7 ent. RNAi protejeazé genomul polikariotelor de infectii virale persistente sau de contaminarea cu transposomi. Descoperirea are per- spective de a fi aplicata in clinica in terapia genica a cancerului si a unor viroze. EVOLUTIA VIRUSURILOR Dezvoltarea tehni caracteristice_bioingin lor dintre diferitele tu gen. De exemplu, virusurle gripale pot evolua prin doua mecanisme: = alunecarea antigenicd, determinat’ de modificiri minore ale icoproteinelor anvelopei virale care aduc tolusi un avantaj selectiv lubpinilor care infecteaza 0 populatie imuna = comutarea antigenica, deter mente genomice. Noi variante antigenice pot fi generate cénd geneie pentru hemaglutinin’ sau pentru neuraminidazé de ta virusurile gri pale ale unor specii de pasari sau mamifere sunt introduse in setul genetic al virusurilor gripale umane. Gena H3 (hemaglutinina) a tulpii ‘A Hong Kong, care a erupt in 1968, a derivat de la tulpini eovine sau aviare. Afectarea major a antigenicitati tupinilor aparute prin Feasortarea genelor explicd patogenitatea lor excesiva gi extinderea pandemicd a epidemilor. © variabiltate gi mai pronunjat@ au tulpinile de virus al imuno- deficenfei umane - HIV 1 - In care caz a fost introdus termenul de Wicd de populafi virale foarte inrudite, dar cu sevente distincte. Considerand un singur boinay de la care, in cursul se izoleaza mai mulle specimene virale, acestea difera intre ele atat ‘antigenic, cat si in privinla unor proprietaji biologice: efect Gtopatic, viulenfa, antigenicitate etc de secventiere genomicd gi a procedeelor ‘au adus 0 perspectiva nou’ asupra rela- ale unei specii sau dintre specie aceluiagi de reasortari intre seg- ORIGINEA VIRUSURILOR Inte microorganismele prokariate cu potent constitie o enttate aporte de parazi umai pasager in afara uportal energetic ( de sinteza pro- teicd (ibozomi) ale cel un genom pro- priu (ADN' sau ARN) care codiioa componentele structurale. 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In fiecare faza a cicl vizibi cel MEMBRANA CELULARA Membrana celularé prin structura sa mozaicata, alcat intre care gi virusurile. Seche: iculelor in vezicule endocitare se numeste endocitoza, jar inter ializarea componentelor fluide se numeste pinocitozd. Endocitoza este foarte eficienté cind succed’ cup (receptor mediated endocytosi acidfica_ prin acumularea. pro F permifand activarea hidrolazelor LINqnio:oIy “1 yuoWBId op uOXe wodsueN :el!Qe}OU JUNs 40} yuns | ‘o|UnsnuinoaL Up ereipewiou ojewewely “aeoqe 1 aiejquese ep ajunoo| ang sojuoioid eeses6u! ul 16 9 sojunenin eovezqeUsoTU) UL UAuOILt RUNDE 9p efelUEUEH.4 “INGMOOU S areIpaUE}U ejueWey "gUNde ep sUAWeYor2IU “SOIgY YeUETEW Bp UNdy 19R SUUCD \nNUELIOHSOUI aimjeu! 3jean einomed 9p (izniou)) ouyersuo ayeBaiBe ezeawsc) yeou) ‘ewepunge @p Wie quns ‘Yo ayjnui op 16 (ayZ0dep) unjood UL ezee!nuiNde os 1080} Ul ojeZnOIUS eoyDIds: STUN sjoulBIo.d “YAS ep redeo uN nD eSeie uns sonsnan ie xpydadyod sowosinoosd ezaqUIs Ul ifelebuE wozoquijog "gunewo%D nujued injnwozoejonu ejeuleioid 1S ninuo, -2J8yS0}0 ejejUOUIEWJ "ywiOzoqu EzeeuNO} aS Jory “eOHeUUIZUB sojun|UE| 3]@ sjuauodwea yuns “(suojoud-o0y) o10q aUo}O1d e\UNU O30 UL aezREWIS e[ouIo|od “aieInjoseAUL sojaIUebIO 1S IRIE UL oWWSe}doID InjrjUaUIEdWOD jmses aImyysUOD amoso19 xSedie4) 19INI89 JOUeKKe Hfezindxe uns seejonuEAUI eiquiese ttuouin aie Ud ajeueo gzeaels 18 epIBL 98) 0 ‘es2Nj20 PUPIqUOW Ul BieSU! 2S B9}S008 ‘In}nUOUIA elfonssuCO najUed ejelfuase uns nu ojouieyoidooi6 e1e> | ‘unsnuin aye ey “eIeIA euunBnwuL 8p Insadoud ezet 1S o1ejoNU pie ‘guIsjo!doajonU :ojeuA oyuauod -Woo ajje|s|oo nsjued osezI/e90) Op oVouNd UIANp eIeINJeo eUEIqWOUI UL aje19su ajeuIA sjeurerosdooH} ‘queAD@y eu! 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ADN genomic celular si proteinele asociate (histone etc) alcatuiesc cro- ‘matina din i: nucleozomil. Fara aborda problema arhice a nucleozomilor pana la cromozomi, trebuie re| ‘nut ca in cromatina flecare gena se exprima transeri tate, Virusurile detumeaza procesul de folosesc polimerazele celulare in sinteza_componentelor propti Papovavirusurile, care au genom ADN cifcular organizat ca nucleo- zomi, deturneazd cu mulla eficient’ acliunea polimerazelor ADN si ARN celulare. Herpes- si adenovirusurile utilizeaza, de asemenea, polimerazele celulare. Virusurile gripale au anumite particularitaji, Ele au genom ARNss(-) fragmentat. Ele poseda o polimoraza ARN in virion. Totusi, pentru a deveni functional, ARN-ul gripal trebuie sa dobandeascé 0 secven{a terminala 5° sintotizata de polimerazele celulei gazda. Datele histologice probeaza existenta in nucieu a unor zone de concentrare cristalind a parliculelor herpes-, adeno- Virusuri), cea ce releva permeabilizarea membranei nucleare in cursul infectier MOARTEA CELULARA $I APOPTOZA Homeostazia tisulara implica un echilibru dinamic intre moartea celulelor si inlocuirea lor in urma proliferari celulare. Moartea celulara nu survine numai brutal, In condi patologice - bine cunoscutul proces de necroza, ci si in mod programat, fiziologic - fenomen descris in 1972 de Kerr, Wylie si Currie sub ‘numele de apoptoza. In fapt, apoptoza si necroza sunt extremele unui spectru, ambele putand fi induse in aceeasi celula, de acelasi agent, ce acjioneaza Ins in circumstanje difente Necroza este un proces ireversibil rezultat din combinarea. mai multor mecanisme ce pot opera simuitan: uptura membranei plasmatice, care survine sub acfiunea per- forinelor (proteine formatoare de por) sau prin hemierea citoplasmel, Jn urma pierderii ATP si desfacerii logaturilor membrana citoplas- ‘micii/citoschelet; ~ pierderea homeostaziei jonice intracelulare, in special prin aflux de Ca?*; Funcjonarea celuieh paraztate_virat 55 oxidan{i - antioxidant Apoptoza este si ub control gent i lotoxice, colule NK; i si | chimici) din medi ‘embriogeneza, ‘endocrino-dependenta si $1 mentinerea tolerantei imunitare. In afara efectului fiziologic benefic al apoptozei, activarea inapropri ala sau timpurie a mortii celulare programate poate coninbui Ia patogenia unor boli variate, incluzand: viroze, boli neurodegenerative, socul ischemic. trasatura constanta in toate formele de apoptoza (chiar gi cele incomplete, descrise recent sub numele de epoptoza atti faza de integrtate membranara prelu continutul celule! moarte pentru incd schimbari sub- recunoasterea $i 2 ore dupa debutul apoptozei 2 adiacente. Astfel au loc: Pierderea asimettiei membrane! fosfolipidice, carbohidrat. In general ins’, neproducdndu-se celular, apoptoza nu este asocial’ cu reactie zare in vivo. In vitro, corpii apoptotici si frag- mentele celulare se umflé si in final se produce liza - numita gene ric “necrozi secundar Tras morfologice si biochimice ale celulelor apoptotice sunt sumarizate in tabelul 51 expresia_unor grut® 4209 9p giuepuedepul eajeVoKOIOV9 UL 1S e9 ‘YelueVBIO) ejfonpU) UL 18 TL Jojainjeo easeyoxzap ap aet sod! jou un eoeo! 7) sey - y se, Bayeou! 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Bzo;dode 190u uIp ez ednp "enpue} “wopueI EaJeP FOAL IM-NAY AND9I08 ezeeno ewZU3 “eluapuade| usBopue ezeefanuopue jun EaeNOe ULE o1WHOUeB InIN-NGY e eI ~senau! 1S En'suaIx® vaLepelBap ase ezojdode © gonLyDoIq COLOyy Jeaseonpoid” no “ouabopue aceon] uopua jaun gaunoe gns ons0b| Dx & 301 a16 nu] Oup @| 1S SoNpOE as “OpBIOUA ‘dv 9 wapuadop ‘hoe sagcid|ap “wns gue} “Aes _s200id| Soqouzua lode pugoysiut “ieonvoo sooo} ‘BReIU) soREUSEHFOHD yUeBI] fpuoydode sopdioo eovewuo)|20n op _evcwioy git eieuco 22 pine wereevente0 Soo Jeverquow e) ourewos easebo.6e| f fovouniquow fowGou eoveutuou| eevequow newors ezcuor Sou earepuei| vz016004| wzouo3N| TEZOLd0dv 16 |AZONDIN SW SLONULSIG rINLYSYEL rs maw, YIVOIGIW JIOOTOSNUIA 9558 VIRUSOLOGIE MEDICALA T adulte (infectie cu HTLV 1) sau jin limfomul Burkitt (infectie EBV). De asemenea, activarea limfocitara din infectia HIV este insojita de hiperexpresia Fas. Expresia Fas este exacerbat de gamma interferon, de factorul de necroza tumoral (TNF alfa) sau de IL-2. Structura Fas sugereazé funclionarea lui ca receptor pentru citokine. Disfunctii ale sistemului Fas au fost implicate in aparitia bollor limfoprolifera- tive gi_a bolilor autoimune. Doua proteine antiapoptotice majore codificate de gena Bel 2 re. Se pare cd 0 gend unica este respon- terme si exteme, Este jonata_ de un promotor spre care converg semnale pro si antiapoptotice. Existé numeroase_pro- teine virale Bo! 2 like, ce par a creste supravieluirea celulara: BHRF = din virusul Epstein-Barr, proteina E1b a adenovirusurilor etc. Recent, 0 conexiune interesanté s-a facut intre procesul de mitoz’ si cel de apoptoza, 0 viziune extrema flind aceea ci apoptoza este 0 mitozd aberanta. Genele implicate in reglarea prol rari celulare intervin si In apoptoza: p53, c-myc, Rb 1, E1A, cyclin D1, cas, p34, cdc? kinaza Sintezi Leziunile viral induse care duc la compromiterea funcfilor celu- foldeauna rezultatul lizei (necrozei) celulare. se produc dereglari ale programului apoptotic car Patologia viral. Activarea inapropriala sau timpurie a morfii celulare Programate poate contribui la patogenia unor boli variate incluzand Virozele cronice si cancerul BIBLIOGRAFIE Klein 6. Virus latency and transtomati 1939;58°5.8 Levy JA. Pathogenesis of HIV infection, Microbiol. Rev, 1993:57:189-289, Wel X, Ghosh SK, Taylor ME et al. Nature 1995,373:117 Cohen JJ. Immundl. Today 1999:14:126, ine stalegy of Epstein Barr virus, Cat CAPITOLUL 6 PATOGENIA INFECTIEI VIRALE sistente (vezi capitol tatul replicarit_virusuri iremica sau soptinevriicd - si afectanii organelor ints. simptomelor este fie urmarea efectului citopalic viral, fie a fenomenelor imunopatologice rezultate din raspunsul imun al gazdei. CADRU GENERAL Cunostinjele privind replicarea virusurilor, respectiy, interactiunea Virus - colula gazda, capata valoare practica in masura in care putern explica relaia virus’ - organism gazda $i evolulia ciclicd a virozelor. Trebule observat c& aspectele abordate in acest capitol nu pot fi despariite de analiza raspunsului imun si a altor mecanisme de aparare nespeciica care afecteaza rezolulia virozelor. Important in patogenia infectilor virale este conceptul re staluteaza existenfa frecventa a formelor asimpto- arente de boala (labelele 6.1 si 61). De exemplu, tn fiecdrui caz pa corespund In jur de 100 de logic major, lasand surse ‘ibuie a difuzarea _virusu care fiecare infeciie este bare Virulenta rezuma efectul variatelor mecanisme prin care agentti infec{iosi igi manifesta patogenitatea. Virulenfa este condifionata de factori care {in de: gazda: varsta, sex, stare de nutrie, rezistenta imund etc doza, Cale de inoculare, pasaje anterioare ale tu vitus $8 circule necontrolat sis: in colectivitate. 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Patogenitatea lor este relevaté numai dupa generalizarea multstadiala a infectiei. Sunt alte virusuri - asociate cu gastroenterite endemo-epidemice - care nu depagesc epiteliul digestiv. Rotavirusurile (din familia reoviridae) si agentii‘asemanatori virusului Norwalk sunt patogeni primari si exclusivi ai epiteliului intestinal TABELUL 61 STADIL IN PATOGENEZA VIRALA eceaul Wr oan gazds mara a. psa DISEMINAREA SISTEMICA A VIRUSURILOR Diseminarea virusurilor de la poarta de intrare se face cel mai freovent pe cale sanguina prin viremie (tabelul 6.lll). Participarea né_a diseminarit limfatice nu trebuie omisa. in cateva cazuri, face pe calea tracturilor nervoase, prin Vom exempiifica diseminarea viremica cu evolutia infect ice (pojanul), Poarta de intrare Wu in fesutul adeneidian ruje- cals un simplu vector, ci gi un substrat cel Virus ceea ce determina afectarea ie bogata: plamani (bronhopneumonia medio (otita), sistemul nervos central (encefalita rujeolica) ‘sau chiar derm (rashul ruj a in aceste “organe {inta" este Viremic: viremia secundara. Amploarea aces- ald de sinteza de anticorpi specifici care contribuie la fectici impreund cu o varietate de mecanisme efector imunitaji celulare, Trebuie mentionat schematismul descrieri’ ante- tioare care nu explica varietatea simptomatologiei rujeolice. Spre ‘exemplu, epiteliul conjunctival a fost creditat cu rolul de poarta de intrare, suslinandu-se c& ochelarii ar putea proteja copii din antura- jul unor surse de infectie. Implicarea sistemului nervos central poate ee Patogenia infectioi vale 63 avea loc pe cai le: prin plexul coroid, prin meninge - ependim lor cerebrale. Fagocitarea virusului de catre 4 traversarea barierei hematoencefa- Virusurile in sange pot fi vehiculate si in alte moduri decat asociate limfocitelor. De exemplu, 0 serie de arbovirusuri sunt adsorbite de eritrocite, parvovirusurile au fost evidenjiate atagate la trombocite, iar multe picornavirusuri circula liber in plasma. In fine, in alte viroze emia este mixta: virusul este in parte asociat elementelor figural in parte liber in plasma, EVOLUTIA CICLICA A INFECTIILOR VIRALE Virozele evolueaza in patru stadii succesive: + incubalia - perioada de la contactul cu sursa infectan’a ta debutul simptomelor; - perioada de ‘debut - asociatd, de obicei, viremiei primare; + pefioada de stare -in care asistém la replicarea in ‘organele = perioada de convalescen{a - care conduce la vindecare. Durata fiecdrui stadiu este caracteristicé virozelor, cu unele vari- in funciie de particularitayi de varst, sex, patrimoni fect sau interventii terapeutice etc. Distinctia intre evol sistemice gi cele limitate la poarta de intrare se refera, contagiozitate (excrefia de virus) si durata replicarit virale TABELUL 61V DURATA INCUBATIE! 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CADRU GENERAL Infectile virale persistente sunt importante din mai multe puncte de vedere: + facilteaza continuitatea lantului epidemic in colectivitatimici sau izolate; = pot fi reactivate plasme; + unele sunt imunosupresoare si facliteaza expresia clinica a tuner germeni oportunisti Fenner si White definesc infectile virale persistente drept condi in care virusul sau, cel putin, genomul viral, sunt conservate in organismul gazda 0 perioada indelungat’ de timp. Varietatea mani- festarilor clinice in cursul persistenlei virale impune o clasificare. Am adoptat 0 impairire in care fiecare categorie in vivo are un cores- pondent Modelele persistentei virale in vitro limuresc mecanismele patogenice specifice flecarui tip de per- ~ infectia cronic in vivo si cullurile echilibrate (steady state) in“WOX9 9p ‘eo ‘owioys's oye Yj “epzeB J9Injo9 nuoUEB UW! 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INWISIS BP RINOSOUNIeA ey Nu eS angen eIeWe\N eh insnaa “pues ezeomjoe) eseo epzeB - sna saifejas aye aialey enop ersixa ‘jeunoysuey} cpMyno gua] Boost - (sy20 sow1e9) axeoweund ayanyino 1S gluare| efo9q ~ YIWOIGSN JISOIOSNEIA 370 VIRUSOLOGIE MEDICALA Epstein-Barr, ADN viral poate persista neintegrat ca care se replica sincron cu genomul cel genomului vial in situsuri specifice ale genomului celular (si nu la int&mplare) are 0 importanfa medical deosebita. Integrarea ADN viral in genomul gazdei promoveaz& mutageneza insertionala. Mutageneza jn anumite situsuri este asocialé cu primele evenimente din transformarea maligna. Din punct de vedere genetic, acest model de_onco- geneza viral fare initiate din cultun transformat nespeciticd. Fragiizarea genomului la punctul de inserfie asigura pro- movarea recombinarilor genetice. Exista situa in care infeclia persistent poate corecta stari patologice preexistente. De exemplu, tn linia de gobolani BB care fac spontan diabet insulino-dependent infectia persistenta cu virusul chor omeningitel limfocitare (LCM) reduce incidenja diabetului. LCM infecteazd limfocitele CD4 pozitive care constituie veriga efectorie a Aspunsului autoimun impotriva celulelor beta din pancreas. La copiii bol navi de SIDA si infectati simullan cu virusul hepatitei B, hepa evolueazé mal trenant datorité depletiei acelorasi limfocite CD4 PERSISTENTA VIRALA $I RASPUNSUL IMUN Multe virusuri persista in organismul gazdei in ciuda raspunsului imun, datorité productiei de variante antigenice care nu mai sunt recunoscute de efectorii imuni, Cu alte cuvinte, tulpina infectanta inital este diferité antigenic de cea izolata in cursul sau in stadile finale ale boli. Raspunsul imun este presorul selectiv. care favorizeazé acumularea din populatia virala heterogend a acelor virioni care scapai recunoasterii imune. HIV este un astfel de exemplu pentru ca rata excesiva a erorilor de transcriere a reverstranscriptazei face cain orice moment, in organismul infectat, s existe mai multe variante (quasispecii) din care cate una devine temporar dominanta sc8pand de supravegherea imunologic’. Evolutia este ondulanta, rand pe rand, raspunsul imun - pana la propria epuizare - reusind s& controleze nolle variante. Supresia unor proteine gazd@ critice pentru recunoasterea infectiei este un alt mecanism prin care se instaleaza persistenta TABELUL 7. MECANISME DE ELUDARE A RASPUNSULUI IMUN CARE CONTRIBUIE LA INSTALAREA PERSISTENTE! VIRALE (Erector i [Mecantame vrale de efo-[Eremple lsare lancom = exraceiar \Varaja entgenics, ——|Lentvrasan lanticorpt biocany lHepadnavirus [ADCO Sau “ACM [ius tavacsiular Latenta vials IRerpesviusu |imunomodulare [Paramixovirusuc Slule T aatonce [Calula Woetate —fSupresia [adenoviuean loiminvaroa [EBV in limfoame mediata de anticorpi si complement Efectorii imuni celulari recunosc peptidele derivate din antigenele virale numai daca acestea sunt legate de proteinele complexului major de histocompatibilitate (CMH). De cele mai multe ori, lanturile alfa si bela ale CMH formeaza o niga (fanta) In care peptidele viral derivate sunt expuse. Alleori, proteine virale numite superantigene pot fi recunoscute independent de restrictia CMH. in fine, alte celule T purtatoare de receptori gamma recunosc proteine nonself aparute urma actiunii virale asupra celulei gazdé (de exemplu, recunosc $i cupleaza proteinele de goc termic). ‘Sunt virusuri care interfereazi cu expresia proteinelor CMH si @ allor proteine rezultate in urma procesului infectios (tabolul 7.1V).. ‘Adenovirusutile inhib& expresia proteinelor CMH; HIV distruge celulele cheie ale raspunsului imun - celulele CD4 pozitive - si altereaza functia macrofagelor implicate in prezentarea antigenelor TABELUL TV UNELE PROTEINE VIRALE CARE MODULEAZA RASPUNSUL INFLAMATOR $I IMUN Viewsat Protena wate [Adonowrasum Protaine Wrnpant ET EZ Poxirusum Proteine trapont 12 complement, antagonit ln [Sicoprcteine ale anveloper [complement anticomy [Sanmanerpeavrisun ——_[Proteme wins Epsien Bar [FN cfomne IRevonnasum FW Ta (eleaua cterneorcaidnsounun fooigns 2] “iugneq e eUEpAe oUEp eIeYA efusysisied ep BeULUDTEP eIBo}O}EWO}dUNS yUenDa!) 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