Class Note for BIOL 220 with Professor Blumenthal at IPFW
Class Note for BIOL 220 with Professor Blumenthal at IPFW
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Contains 2 identical RNA strands 7 7000 to 10000 bases long 7 RNA is capped and polyadenylated 7 2 identical strand function unknown I Speculated that it may buffer against a too rapid mutation mte due to inaccuracy of RT o Order of genes in Retrovirus R sequence 7 Present at both ends 20250 bases long 7 Important transcriptional signals that are only used in provirus U5 sequence untranslated 7 Does not encode protein 75200 bases long 7 Has cis acting regulatory signals PB Primer binding site 7 Specific tRNA primer for initiation of transcription binds Gagpr0tpolintenv 7 Gag encodes coat proteins 7 When gagprotpol in same reading frame they are expressed as one precursor protein that must be cleaved by protease 7 Gag expressed in much higher amounts than gagprotpol Q There is a variable length sequence following enV 7 Contains polypurine tract PP important in generating DNA from virion RNA 7 Untranslated sequence U 3 7 2quot copy of the R sequence Two different types of HIV 7 Mtrophic most important in initial infection I Macrophage is initial target I Individuals Who are homozygous for mutation in CCRS are extremely resistant but NOT immune to HIV infection I Individuals Who are heterozygous for mutation in CCRS are less susceptible to infection than normal people I HIV integrates into macrophage genome non dividing terminally differentiated cell therefore HIV cannot replicate Within macrophage I Macrophage acts as trojan horse in bringing HIV to lymphatic cells 7 Ttrophic forms made by mutation in macrophage o CD4 with CXCR4 coreceptor chemokine receptor become infected with HIV in lymph nodes and other lymphatic tissues I T cells replicate Within these tissues to try to respond to HIV infection I HIV is continually being replicated in these T cells and as cells are killed there is massive stem cell proliferation to replace the lost cells 7 Increase in level of opportunistic infections begin as T cell levels drop to below ZOOcc FIGURE 2 1 Viral Repljmtirjm in Huma Lquotr1 rqf rhquotmyT95 Scjanr ling ale1 fmn J39nim39mgmph m Hu39mquot ir11 elz1e h L ma n Tail I39r r39ar1 jg39t i A squot f EH mf ijted with HIV SlimVir lg vima par tidcs and WarmWIN mm the CM mrfam magni ml RIDGE HITWESJ B Enlargement 0f 31 23L rtiu r1 31313193 r IM39JLIE ILEIFI lE CE SUFFEIE39IP in A 395m1um39ing HTLEIIH JIE virLJE 1 a1r ifla E39JLIE JEJFIE mt f Ih LE1 ELHI fiZJL39SE I39j39mazigni rjd EIGEDDD t mEE 315 eatjzh HIV hfl jelly it legims39EE a hale in 39th Eff m mbran 1Pf liajgraytm Tammi f quot quotaga hfrrm Frugmn39 HE T Z1MI FEJH friutj39w J CIFr39ird rft f Tamer H ESESW Fa 171quot I r39 fagI HIV 1998 In 1996 deaths from AIDS declined for the first time in gt 10 years i Due to powerful therapies that retard the activity of HIV 1 AntiRT drugs protease inhibitors cocktails 00 Trend in industrial countries not representative of the world as a whole 39I39Expanding rapidly thousands of separate epidemics 00 Since early 1980s 40 million have contracted AIDS and 12 million have died 7 Nearly 6 million people 16000day acquired HIV 7 23 million have died from HIV disease including 460000 children o More than 90 of HIV infected people live in developing countries but gt than 90 of the money spent for care and prevention is spent in industrial countries o HIV therapies cost N 10000year per person not available in developing countries 39 o The region below the Sahara in Africa has gt 23 of the globe s HIV infected population and N 90 of all infected children 7 In areas of Botswana Swaziland and several provinces of South Africa one in four adults is infected 7 Life expectancy is falling in Africa 7 Unprotected heterosexual sex accounts for most of HIVs spread but also due to contaminated blood supply 25 of blood is NOT screened for HIV and this is administered to women and children 39 India has 35 million HIV infected people o HIV is spreading into Thailand Burma and Vietnam and China o Epidemiologists have found that 7 Groups Whose human rights are least respected are most affected 7 As epidemics mature the epidemic shifts from the primary population to those who were socially marginalized or discriminated against before the epidemic began gender race economic status culture religion o In 1988 whites accounted for 60 of infections and blacks and hispanics 39 7 By 1996 38 of new cases diagnosed in Whites and 61 in blacks and Hispanics 7 Between 199596 AIDS declined 13 in Whites but not at all in blacks and Hispanics o Future 7 AIDS Will become more concentrated and expand faster in developing countries 7 HIV will enter areas Where it has not been seen before 7 Will slow in industrial nations for some populations but increase in marginalized groups 7 Cost of care Will rise dramatically 7 Highest priority must be given to finding a vaccine and making it available to those who need it most amp also to educate those people who need it most o Until a few years ago HIV infection was invariably a progressive lethal disease that robbed its Victims of dignity 7 Most medical interventions focused on treatments for pneum onias and other opportunistic infections rather than controlling HIV itself 7 Since 1995 advances have led to a shift in prospects for most patients who get treatment 0 Between 1996 and 1997 deaths from AIDS in the US declined by 44 7 During same time hospitalizations due to AIDS related complications opportunistic infections also dropped 7 Due to intensive cocktail therapies I Can this be maintained No long term data yet as to how long AIDS symptoms can be delayed with these therapies I Treatment is COSTLY I Some people do not respond well while others do very well 0 Ultimate goal is CURE not maintenance 0 Management of AIDS is real but a CURE is probably not possible How HIV Harms Spread 7 Sexual contact 7 Direct exposure to contaminated blood 7 Mother to fetus vertical transmission through placenta and through milk 7 Contaminated needles 7 NOT TRANSMITED BY I SALIVA KISSING UTENSILS HUGGING SNEEZING MOSQUITO SWEAT o HIV infects primarily CD4 cells Helper T lymphocytes but can invade other cells macrophages dendritic cells 7 Replicates and is transmitted to other cells o Severity of infectious symptoms and expected life span after infection depends on infectious viral load o At start of infection there is a high level of viral replication as measured by viral levels in the blood and by a drop of CD4 cells CD4 cells normally are about 800 cells per cubic millimeter of blood True AIDS occurs when these cells drop below 200 About 3 weeks into infection acute phase many people display symptoms like mononucleosis 7 Fever enlarged lymph nodes rash muscle aches and pains and headaches 7 These symptoms resolve in 7 3 weeks as immune response begins to control infectious process killing of virally infected CD4 cells by CD8 cytotoxic cells 7 Antibody molecules produced L J SE x 7 v Emu quotif mm 1 SOURCE u 4 Anthony Fwd 81 m N Anna s cuf Internal Med r if i 3 24 I J YERRS 996 a WEEKS x k 2 8 9 101a m J a M H H u j I 3 0w CaRcwggPHASE I J lt gtr POPE 33 mag imm 3x EE Fi Q E P9352 o By siX months rate of Viral replication is at a lower but steady state 7 Seroconversion antibody levels detectable and can be measured by ELISA at 6 months 7 Level of virus replication is patient dependent and will determine the subsequent rate of disease progression I Generally 810 years pass before major HIVrelated symptoms appear I Chronicprolonged phase of infection 7 Over time CD4 levels gradually fall When less than 200 cellscc patient has AIDS HIV is able to infect cells other than CD4 7 In addition to the CD4 antigen there are other coreceptors to which the HIV binds I CCRS found on macrophages I CXCR4 found on T cells 7 If these coreceptors are mutated on the cells then HIV is unable to adsorb attach and the individual is resistant to infection o HIV replicates only when the infected cell replicates 7 When specific immune response begins specific helper cells die o HIV mutates at high rate and immune response cannot keep up with antigenic changes after 1012 years Q As CD4 levels drop below 100 HIV levels in blood increase 7 Bacteria that are normally contained begin to proliferate and cause opportunistic infections I Pneumocystis carinii and toxoplasmosis 7 Once these symptoms begin to appear the patient usually has 12 years before the disease is lethal 1175 5MB r V continueswmthemva and change antigenicity of Vll uS O AntiRetroviral Drugs 7 Block viral replication in two ways Inhibition of reverse transcriptase prevent integration into host genome by preventing RNA DNA transcription iNucleoside analogues resemble natural nucleotides but prevent completion on growing strand AZT 1987 zidovudine Inhibition of HIV proteases block catalytic site of HIV protease preventing it from cleaving newly made HIV proteins o Early beliefs of HIV disease 7 Suggested that only a few CD4 cells were actually infected and that HIV replicated weakly for a long period of time I This view implied that most ofthe lost T cells were killed by a mechanism other than by HIV replication if this were true then HIV directed dmgs might not be able to prevent this T cell killing 7 It is now believed that HIV replicates fast from the start I HIV levels remain stable for several years because body responds by making very high levels of CD4 T cells replaces those that are killed o The strength of the initial immune response has a significant effect on progression to AIDS 7 Those who respond with strong CD8 activity get greater suppression of viral replication early in infection and progress more slowly towards AIDS than those who mount a weak response 7 A strong initial response helps to later manufacture the subset of CD4 cells that specifically react to HIV I Once these speci c T cells are lost they may not come back with treatment even though other CD4 T cells are made to increase T cell number to greater than 200 o At any stage viral levels correlate with prognosis 7 Patients Whose viral levels fall into the undetectable range and stay there are most likely to avoid progression to AIDS o Thus the amount of virus in the system plays a major role in determining a patient s eventual outcome 7 Therapy aims to shut down viral replication 7 For those patient s Whose immune systems are suppressed this is best way to keep viral levels down 7 All patients must stay on medications I I 1 it 3535 3mg 3333 W 39 T53 rttfttttitt Wt t t tPtt tt ttttttt39t ttt Atttttttttt ttt ttttttttttttt t tttttttrttttittttt fmg w V 39 U f tt ttt39ttttttttt 0f RNtttH I tttttttttttt tftDNA I t gt TR ttttttt ttp t 16 R U 3 mt 39 WM t a ttt tttt t TH tt It tttittt tft tttt ttttttt ttttttttt39ttttt tttt quot W t I tt ttty tt alters plasma I I 39 J quot J tttttttttt ttttttttt tftttt of t ttttt ttt39 ttttttt tttttttttttt tftttt tittt mitt 0t 39 ttttg ttttttttttpttt ttttt ttt tDNttt39 t mwmmmm t tttt t g t tttt ttttt tttditt tgtttittt tftttttttt39ttt DNA it ttt t i t tt ttgt tfttt t a 5 t l tttt Ttt39t it t V a tquot 3955 t ty Ravage ag aepn y Gplgi y 39 U T 5 t 39 39 39 appat a tus 39 t x 39 I 39 a tranacrrtptase t V t t H f t ttt39ttttt ttttgttt LTFt 1 TH Tra39nstla ti rt tanf j at wt 39i Wtquot J ttttttttttttttttt ttqttttt tttt tttttt tt ttt at t39 it tutttttftt tttttttt tttttttttt t 0f t t V l t t t Mtg39t t tt ma pt t tttt M r to tftDNtt t 0 W 39 n akz Vitl Nuclear translaca timn E tt tttt39tt39tttt tNtt ttttttt t39ttttgtttt tttt t ttttjtt tttt ttt ttttttttt tttttt ttt tttttt tttttttt mtttttttttt w 1 I a Ttt tttttgttttttttttttttttttt tt ttt tttttgtttt ttttttt tttttttttttttt39w ttt tttt tt39ttttttttttttttttttttttt M r J A33 1 it tttt TR tttttttttpttttt ttttttt39tttttt tt tttt ttttt TR tt tttt tut t tttt ptttt39tttt t l 2 Hg quot 39 W 9 Cell g ar ttgmit DNA r mm x tttttttttt Fttt l trtmttttttntttmctttttprttetmtttTtttttttttttttptttttttttttttttttttt tttttttt tftttttptt39tttt tttt ttt39t tttt tttt tttgtt tfttttttt tttttttttittt 6 tttttt ttt tttt tttttttt it tttttttt ttttttttt t tr tttttt ftttt ttt t39ttftttttt til I t t f Gymtz ta m o Optimal Therapy HAART ighly ctive nti etroviral herapy 7 Consists of triple therapy I Two nucleoside analogues and a protease inhibitors 7 Dosage ofpi11sday empty vs full stomach side elfects etc may be too much for some patients andthey stop therapy 7 Least number ofpills is 8day and most is 24day I Cost N 1000012000year v AntiHIV Drugs Now on the Marke 39 91 t m I A u v au u v A v v r pA quot 1 39 pv V I 3 V b m firI V39 3 L r w 39tv v A 39439 7 h 39 a I 39 3 ESE i n Ear v 39 u quotquot39quotquot39 1 739 quot r quotv I uvv 1 17 iqltL A I 39quotII may V V V h Reverse Transcriptase Inhibitors Nucleosude Analogues viciemddn i 2 pil ls2 39 7 39 Dquot empty Sthmach 39 Vij g V v 39hVE39Ul39 pafthf 7 39 quot Lammdine EPMIFJTCJ39 39 TEp39fNthimesaday 394 V39 7 Usuaily39nune Stamineizeritdt lT Tlpillrz ti mesaday 7 PeriphErameumpaw Za39dmbme HINDIWC 1 Pilh339itim93 Eda i39 C 1 quot f Peripheraln umpathymamhi ar 39matiom quot V V V V 39I 391 V V V V V VV V Ipantr aticinflammationj VV V V ZidamdineRegtroviizAZTJ39 1pill 2 time39sEda V r V 39 V Nansemheadachean mia 39ne Utrop39enia T du c d levels 1 39 L r 39 v A Vofneutmphillwhitebland cells weakn e55 inscmni a V39 39 Pill canta inlin39g Iamivudine 1pi1ltL2timesadayr 39 V Q 39 same aisfarii dmudineg quot and zid vu39dineCambium 3 quot 39 39 39 39 39 y Reverse Transcriptase Inhibitors Nonnucleoside AnaIOQues De la rdineRestrimr i 4 Pi1395r3 time adavvim39ixEd i tdiwaferlinet7 Rashrheadath Bahama 4 39 39 Within anh ur ain t agidgs or didanpsineVV VV 39 V V V NevirapineWramun l39i V 1 pm timas aiday j j 1 V Eaghfhepafi tis E Pr ut ease lnhibii39t39urs IHdinaV39iiv39ICfixiVanl 39 2 PZ39illSIj3tii39h25a39day 7 Kidneiiist nESQhauseahead39aCheblUrrEdA viSidm 0 Gummy stnma ch chi thaMWfatgsnack u dizziness rasgh metallic taste inquot Mouth b39narmai 39 l andnot wi thinzhours of didancsine 39distribgu ti niaffat ElevatedItriglycr ride andchqlestemf 39 r 39 quot 9 Jl39evelsgglunseintulerante V 39 werfinavirlzwraCep t 39 39 Splits times day F Diarrheaabnurmalfdistributi an offa televated 39 39 V I 39 i with some fend 39 I g V V triglycerridequotaridcholesteml levelsglumseintoleranm Ri tonaviriNorVir A 5 pills2timeafday0r4pflls Jtimesaday Nauseavomitingdiarrheaabdominalpainhea39dacrher v 39 39 if taken39with Esquiinavir with foadand l39lf t39 Vprick ihgSehs ti jh skinhepatitisweaknegg 39 V g within 2 hoursa fdida nnsine I 39 39abnnrmalidiStrib39UtlonoffatgelewatedAtrigi yCEride and39 r h alestemlflevelsrgluwmintolerance quot U quot 39 quot Saquinavirtlnvirasaahardgel 6pilis 39timesa 13erpillstimesaday 39Nause Va iayVrhigiamadameabmrmaldistributim f apsuleFortovasaa 39 if taken with ritonavi with asiargem aja fat levatedtriglycerideand chaale emlAIVEWISVQIUWSEV Sa 39QEJ apsumm 39 t W 39 intolerance quot m a 39 39 As cf April 1993 V5 hl E If1 f gt V aquot 39 quot quot 1 quot 39h l h r W 1 39 igt 139I EE Eih LHGELEE fmh an and gum1215 m3 rm 39 39 39b SUM FILMS r a a Aquot I 39 y 399 h l Iv us a VJ 39 n I a39 I a L I v 3 1 J 739 a 7 ii a a 39T 1 25m 1 E iltETa m gusm i tun u il hl mam guah and Ema Eth firs anztj3u gs 54213 unit 34 31 jamL t p g quot u a 13 1 39 1 z g i 2quot i I 1 39 r Irma333 my hats L3 be ziemamug am CG J E CAamp M 15 Lu mu 1 Fi tiu mu 3 mmuawr L i menu1 Mgr3 m H 39 39 139 1 amp amp 133 mud 31 my imam aiwh ma ICCBW mantmi w 25 m my Aymara 513m piann 51m an at my 1336 HEL LEQEIT iiajw Lawmmm w39IA qquotv P davquot PI y quotp 1 39 4 rim s amp lsv v v I l lE I t 1quot i L 1 H 39 3235 41 5343 33m E i vt uh m is 11 33 Empty t zm auu EBI HE um utmmvn 111 BEL 3511 THE 1 Luffs imli39 Hut mi il39 in 41313 F j 3 a 14 3quot n 1 y nn 111 1 ir39 fl quotlit DI51 1 i l I L V quot I 3933quot quot i i quot39 r 39139 39 i 1 quot it Ila5 2 quotw I 1 u E H1 1 w in 3 bit E3 hii ilidh L533 11131 EJJ ULJVE39LJE Hr 1L awful3 illEul U39lL39 a 1 uduili v CM flint113 Eatielhld I m3911 394 13 aliial Lin an t39L Hit 112 quot3quot 393 H 39h H 39II 331 1 1r if an ii 1 39 rm 2quot I l U ln i a Fi quot 3 53 T x I t 139 l l v I L I I Prdtgas u 13 r b u U m n u n J r i a i a quot 1 I f p a irL Urat e 13 V ltFn 1 A 9 if39AfY w 139 2451 r I 4 h 9 1 2 3 114 25 I 4 g 539qu 1 n v FITquot quot1 l i 4Priatea 49 a in 3 39 I 1 5vf V 335 J 39X n TL 1 3 I b 139w m ftrf aglvu u y 2 44 1 3 SE quot V l p JV 1 F U E L 9 3 1393 a A l V quot7 ugg39g a l l F 71 A Ek y F 1 r it A I z J m i 1 4 1 Lw n T39 39v i n V 1 ESE t A Brut 4 Y F A I rt 13 4x lV W I u 1 fist 4 4 rtm lv 9 rquot l lquot v7 n r 9 tr 5 s m m a j 31 L z an x VIV wrr 39 i 393 r 1 h r593quot r b I 5 J EDIE quot 397 quot r 39 I j p I 1 If i p l dd aha x Ema H J I we Hi 5 i 5 v r v 121quot n 5 39I v n u 1 SEE I 4 n 5 I 7 l A v J r l J 7 Sir fl 9 z t i u I Stair 3 E T as d b I I Y Rquot in39h ElfE5 i 39i t tr ci r 1 y 1 r l o anscr 139 I 1 I Epf A taSe AJ r A ft aflquth lt A quot WI m as o 1 f 1 v s u l x I h FE in 3 hi EFSE tr bTit er n r I I t I I A r a r1 1 a v 4 v vv39 7 J h v x v N I f k L 4 stri 39v a I y a 39tjaSE f 1 f Eld 39 RE I v trim vu39di is 1 I E g 3 k 1 REE 39 irih 39 E 39 we r 1 via l l g q l I x tn 9 t J V Ei39SE39 6 PE 5t ijical PEUt C lS far KPDSIZIIE reventl Drug Resistance o Mediated by mutations 7 Nucleoside analogue resistance may be caused by a single mutation to reactive protein 7 Protease resistance to drugs usually requires at least two mutations in a single gene o HIV makes N 10 billion replicatesday 7 Done Without accuracy genome of each new particle probably differs from parent genome in at least one spot 7 Thus every mutation able to contribute to drug resistance is likely to be made in some of the particles DRUG BINDING A v U E SITE 1 V PHQTEA SE EXIST MG INHHEITCIH Thus if patient has never been treated any compound that is given will encounter some HIV variant that is already resistant If antiretroviral drug taken drug resistance can be attained by only lt5 mutations in a genome will block not variants but resistant forms will proliferate and some of the semi resistant variables will continue to divide and allowed to generate other mutations towards resistance 7 Antiretroviral drugs will select for variables mutants 7 Use of polytherapy vs monotherapy lfvirus is detected in blood after 46 months of therapy then probably a variant that is drug resistant Must alter therapy depending upon the resistance type found Viral levels assessed by viralload assays which count copies of HIV RNA in a milliliter of plasma The number of viral particles is 2 the RNA count 7 Current test sensitive to RNA concentrations of 500 or more copiesml 7 Within 1st 8 weeks of therapy viral loads should drop about 10X by 6 months undetectable 7 Triple therapy successful in 7585 of patients Viral load tests measure viral RNle7 Number of Viral particles is 12 the number of RNAs found why 7 Each viral particle contains two RNA strands In 1996 researchers examined l600 samples of blood from untreated patients and compared viral load with prognosis of survival 7 Found HIV replicates at high rate from start 7 Found viral load directly correlated with survival I 70 with gt30000 copiesml died Within 6 years I Iflt500 lt1 died in 6 years average gt 10 years PATENTS SURWWNG PERCENT I r 39 L Jr 30 Q1 C3 82 20 quot WNITIAL WEIiii LOAD HW RNA mpies pier miHHer of plasma 500 501 TO mm mm TO 10000 1 001 TO 3900 1 30300 2 E 4 YE RS AFTER WRAL LOA 1 6 WM MEASURED o New challenge now is to identify cells that contain provirus resting T cells in which Virus does not replicate 7 Current drugs do not do this 7 To develop these types of drugs researchers must develop new viral load assays that measure infected cells I This Will allow for measuremenw ofsuccess ofneW treatments to eliminate proviral cells I these cells would have no markers speci c for Virus how would you nd these and identify them Trial patients versus field Clinic patients have different results 7 Trial patients have 7585 success 7 Field patients exhibit 50 success I Field patients more heterogenous I Field patients often start later in disease process I Field patients often do not follow protocol andor stop when they feel sick I Field patients may have been on antiretrovirals previously and contain resistant forms Even successful therapy does not restore immune function totally 7 Mix of CD4 cells may be abnormal may not recognize as many pathogens or may be less effective Resting T cells with provirus are not killed by current therapies 7 If become activated will replicate virus 7 Certain cells act as reservoirs of HIV I macrophageshort lived brain neuronslong lived a How to activate immune system 7 Immune cells must see antigen to destroy cell I Give substance that activates infected cells 7 Give HAART to prevent other cells from being infected I Remove stem cells grow in vitro and add back I Remove stem cells add a gene protective against HIV grow in vitro to expand and return to patient I IL2 therapy only cells with IL2R T and B cells o Other Strategies for preventing infection 7 Block integrase enzyme 7 Knock out Zn from protein that needs it in order to draw HIV RNA into new particles being made in cell 7 Use of antisense DNA to inactivate two tar and rev that are necessary for manufacture of other proteins 7 Block entry into cells I Must bind to CD4 and coreceptor proteins I CD4 blockage not very effective but blockage of other coreceptors effective SA Sept 1997 7 Use altered designer virus that infects HIV infected cells and kills those cells HIV Vaccines Natural immune response that vaccine elicits does not destroy HIV in cells 7 Will serve to block HIV from infecting new cells humoral arm of immune system No vaccine made yet to activate cellular arm 7 Will act as a protective mechanism for infection 7 Cannot immunize with vaccine against all variants of HIV 7 Danger of using both Whole killed viral vaccine and live attenuated viral vaccines O Best vaccine Will activate both humoral and cellular branches of immune response HIV env protein is a gp160 7 Composed of gp 120 that interacts with CD4 protein on TH cells 7 Composed of gp 41 anchors gplZO to membrane of HIV Antibodies to both gp160 and gplZO elicit Ab formation and block HIV infection in test tubes 7 Only recognize strains from which they have been made not other strains I Antigenic sites may be different between lab strains and patient strains I Difference in coiling may expose hidden antigenic sites that are not protective in patient strains 39 o In vivo strains may have surface antigens that are highly coated with sugars that would serve to block the ability to recognize antigenic sites o People who are infected with HIV but remain healthy make a very small amount of antibody which can neutralize viruses from many different patient isolates 7 If understand differences in antibodies made then might be able to develop vaccine for HIV Making a killed virus vaccine requires a rigorous inactivation procedure 7 Residual genetic material may be dangerous 7 Harsh treatment makes vaccine less effective 7 Inactivation may cause HIV to lose its gp120 and make it less effective Envelope proteins embedded in pseudovirions empty lipid shells To make T cytotoxic response must associate Ag with cell membranes and self MHC 7 Viral gene inserted into host target cells by viral vector ENWROTEIM GROWN Hw DRY l quoth 39 39 1 TV I in E3Eig 1JFi r rv n quot j W 7 z V M39UN W quot T M z39 Y 3 I nH ls w 1 Muzjn lquot 7 I l 1 r k wq byu whwr w l mm Jhrty l L V I E GCKSHW FROM r h J 39 quot I Il I l I r 339 HV 39 7 k m tr h nn Mun villi 39 law 39 Aw quot h v i 1 39 39 quotM 39 39 yawmeuu l a zuuneurnn va H 39 vmmch ih rz FC v u 139339 v gmwyi v manhunt M jrm e u zwg w gt 1 hr NH lwa r I quot V 39 39 s I quotH V 439 F r I nhffi39 h N Uv 39fwwrtM 35quot 44s i h I sumvtwnun w quot b 3 Mann nHvquot Whig quotf HHUJ IwH 3quotquot quot quotH V Q FV quot397quotquotquot39 quotJwgo 5394 H Hii quotmquotquotquotquot x aquot 139 l b H higf i Humqthvh quotIb r39 t quot quot 39 Mr391 MMV ff uid H r aw 7 Hum gm warnIf M39jva Fur I w 39f394krh39 l il OI4 39lIJF quotWquot Hquot Vh n39d vgity 39 39g p hg f njn tlivLIIHQF4M LIIdvwil VW IH39H39JHN 9115ix W quot9quot 4 Jquot 3 quot aLmLl v llrquot1 II a4 I VF J W n 4511 39er ts i39r i 39 ilquot x r 39 quotUHHUHH Ieawru39n niwwnu n 39 i ll H w aHHuMmdnn w v y 39 39 i 41 Afl I w any391 39quot quotquot39 quot 1 u mumsnu 39 V Hyny 39rr 5lIVIP b anH H39WHJ 11VJ FF l ar ryu Uquot gtr r I uar gn I quot I u39 1 39 J vta Ir vby1l39 r 3 arxiur 1 l IL T 1 dz 39E E 39 x quotr if Qquot t f 1 1 rum 7 1 q 11 kaPL Il jik ray hJ quot I Luti in Fl quot1 r I H I quotit39ll I z 1 i I 39 Elir l v i kh h r an ab 7 E 5g 5 a i nk 71 i H m uaud lgi i E u I H L H Most common Viral vector being used currently is the Canarypox Virus 7 Canarypox is defective and will not multiply 7 Genes for env and gp120 and other nonsurface HIV proteins inserted into canarypox gag and protease genes 7 Have proved safe in human testing and have elicited a modest TC immune response I Need to have Viruses that cause production of larger amounw of HIV proteins 7 Multiple shots boosters o Other researchers use of Viral peptides 7 Does not elicit good immune response I May be degmded too fast LL BEEDMES PHIMED TD ATTACK HIVINFECTED CE CELLS f EDS TCELL L L E pr D m E F W I NE E FEW GE FD Ei i I R A EAHAHYPUK in d 1 52 55 nu Injection of naked HIV DNA 7 Does get into cells and direct production of viral proteins I Does seem to cause production och I Must evaluate safety and effectiveness o Combination vaccines 7 To activate both arms of immune response I First may be exposed to canarypox virus carrying env to stimulate cellular response I Months later receive pure gp120 to elicit antibody Rx 7 Need to improve delivery system and strength of response use more HIV proteins g I l a a u u r gt r tv39r rv J ppacx k t 4 VH uV 1 pi 114 quotv H u43quot39 V u 1 ff 7 n Lh1quotquot iy Dy gt 4l 39ty H 71 J 390 4 4alv 39Lw v pu h a a u Mr v ludr I l l H quotquot r4 I quotquot39 v J q g 39c q39 a A ag n39r d gt p r dvquot quot A gt1 w 1 w39quot r 15 g Vaccines Eliciting AntiHIV Antihudies Faci3ne lziicit e an bodies have mnmrfmmm l A faisied tnrieccgn l ewaram patients 39sulchas gp 397 1Jf39i39 WhithExaiminv safatyT39j39 l l I 3 TWWEII HIIEHHW 39 7 N Wquot efs fud 5 5f F 3395 5fh uIdf r s ntzHusurfate i Szlightir iskthatpr paf ti smight 39 l MinqhumanSp l 39 pmteinsiinaiir39 liatWEJyinatu ralv incIjudeysamgactiveviminactwatedi Im f rm tlrji lsgi pl f 39 39 1 3 virus mightvshadzits p rnt eins and i r beggm eina ac ve fiinf39 r l tEEe39lylTn mral lalgngigrm abiliwg I q 1 f IPSEiUd lllriiDnS Cl sEtn phaSEltrniralS iPres mr Hll 39 f t p r f ln l iwltlwmucea dm mme I Vaccines Eliciting Cellular Responses quot 39Li VE39FE W I II s s t7 g Phasili39trjials Mak fEicai whicmlgamnu39nt 1 UC timpifcated t prepa39recurrent lm lHllmmes 1quot Ll f 5quot z5 af dl iin idi f tWlf lPW EETUS39 41 1vactineselititmadestimmune7 7 z 39en adingHIVIIrotEinsiuf 39 quotff 7 I V I I H W NLakEdD Hnv 39 g InPhasezlfriails 7 3 f 5 5 Simpl a dm penswe E Same w rryvthatintegfati n EIwa If I V E 39 39 quot3931165i itnhuman39cellsgguld39harm39g39 Patientsj 2 39 l39espons 39 mntainirig n hmmme W 39 T pra pairef ngenes i g 9 j l 395 preptides I i7 L 39 Ih WEE 39 7 V1quot imam E 39 D 39n t alignstrangfrmmufn r SP SE MuratEmmanfragments r 39 Vaccines Eliciting llrllzilzwzuzhur and Cellular esponses l H V I I v r l C mbi ti i i f39 W i WWW 5rl3l 7 Pf 539fSh uld stimlllaita bath warmsnf Cnn p cat dtapr39epare 39 39 gp12 prateinplgus quot 3 jigi g ggiv 39 Eanarypnkmctar 1 gt Li gatten uatedHaw 39 NGtU dEl Stu lF ll if39 3 MagiclasglyjmimigsquotHmmay Virusmmd patentially causequot cliseaie j 39 I v humansbeingass ssed imagrfeutewithI nfertigausiwsr Q r inmnhumah Primates 39 ah iliwm irepl icatg I v El IM mm HIV Migraines Pmspecrs and Challenges SCIENTIFIC AMERICAN july 1998 21 39 Use of live attenuated vaccine 7 Must delete genes critical for HIV replication While maintaining antigenicity of virus 7 Recently a group of physicians volunteered to be given an attenuated virus so that the response process could be monitored I Volunteers feel that value of testing this approach outweighs the potential risks to their health 7 Attenuated SIV in monkeys I Some have proved very effective at inhibiting disease progress ofviiulent strains ofSIV I Protected monkeys do NOT have high Ab s or Tc cell activities so basis of immunity unknown 7 May be combination ofAb Th and Tc At present there is no proof that vaccines will provide longterm full immunity to disease and may even lead to disease Vaccines may give body a head start for protection and thus lower initial level of viral load Wide genetic variability of HIV will limit effectiveness of vaccine I HIV from one patient or one part of the World would be different that from another o Vaccine use will not be available for at least 5 more years 7 Phase III trials necessary 151 HIV PARTICLE isting drugs traverse Some ex inh i INFECT ED CELL tase 39P J transcr Some existing drugs bit protease TRANSCEWSE fundet 739 39 studmuld I39D N 95 mg blackbind m H P HHIHI 5 Scmwrmc AMERICAN July 1998