dnterface deals wit the waysin which biological ‘knowledge is used in our everyday lives HIV ana AIDS Could stem cell transplants provide a cure? Human immunodeficiency virus causes acquired immunodeficiency syndrome (AIDS) — a major human health problem. This Interface outlines how the virus infects white blood cells and examines whether recent research on stem cell ‘transplants might provide hope of a cure 1V infecton/AIDS isa disease of the immune system that is transmitted predominantly throwgh sexual imercourse. In 2010, ¢ affected more chan 34 milion people worldwide and is considered tobe a major health problem in many parts of the world, especially sub. Saharan Africa and south Asia, There i curently no cure forthe disease, which reslted in almost 2 million deaths in 2010 (ee Figue 1). In developed counties the disease is controlled using nuivizal therapy, which usually inhibits Key enzymes lnmportnt fr veal replication. variety of drugs that target cient stages in the inus hfe eyele mast e taken ‘combination frthetherapy to beeffective Anti therapy in developing cures ses widespread osrng tot high ‘ost and the complesty of the treatment egies ‘What is HIV? Human immunodeficiency virus (HIV) Is 2 retovieus This clase of virus contains RNA as ite genetic material ‘When a rtrovieas infects a ell the RNA is tsnscribed 9 SubShacan Affe, North Atria ane mice east South and scutes sia Lin Amerie Eastern Europe an central Asia North Amesca Figure + iodide deaths per year de 1 ADS September 203, Keywords @ Deen Wie ocd cet erovinie DNA by the enayme reverse trnscriptte, This viral DNA 's then incorporated into the genome ofthe host cell (se Figure 2) Once incorporated, viral genes are converted 10 messenger KNA (mRNA) by tanscripton. The mRNA then travels tothe ribosomes ofthe host cell where the process of translation resus in the formation of ne viral protelng. The poetry Correceptor cel sxefce protein tt forms an adiona bar wih sarang molec aad attached primary rece Genome The complet set of gertc tril of an oxgeisn. Gtycoproteln A proen contain covalent ataced carbo omozygous Beating two copies ofthe same leleat 2 partes gee as Pathogen Anicoorgpnin that causes diene, Bam Bo Baw 7008000 7505000 7006000 Deaths per year1 Retrovius ttaches tothe hostel membrane: RNA ‘Sed enzymes a leased cellgtopleim — bythe enaye reverse Varsaiptas ‘etepasm Figure2 Repieation of HW virus viral DNA is alo replicated and passed on to daughter cells ‘whenever the infected cll divides HIV particles are spherical and measure around 120m (ove Figre 3) They ae suerounded bya vial envelope. The of phospholipid bilayer taken frm the host cell membrane. The envelope is ervelopeis a complex structure consis rod eee 3 Viral DNA passes Ee Ee aigenome =) —__ Host el ON crops — formed when the phospholipid layer surtounds the virus pan Sucre becomes detache from the hos cell membrane it 4 proces called budding, Cyeeprotsins embed inthe ‘ital envslope enable the wins particles to bind with and fect neve hoa ll esas they ae released ftom the host el The whole ‘Ae como of he bla hat fram haenatopatec Stem als HS). 0 man cel ines rie rom these tem cal: mye cls *ymphod cals Themed cel ie aves se basa eosnopis and neutrophis, named afer testahing characteris and moneys, wich develop zo eerie ee Bosra Figure A. types of bood cell Sees at ol 28, No. & Bp. 2-6. The paca ne roses imports, which lee cl, Thepe cls {cote ane econ eels (CD88 cals pre abodes, een clare inveredinacbatin of ther mph Teal ao destioy ek that hve cere ected WE Ue (© eee @-- oer Ce Pry ae e e@9 @ —@ Netiopni Fonmeki mei ~_ ae @ lyme al sma iymphocyte 1, eo 89 @ Groton Teel Thelpereall, Beal (Wenroyevios _(acvater sre (makor Inferedcels meditesBealsand artbosies) andtumeurels)"eytotoxe Tels) 16 bloga eres een®, x * Figure 3 Cloured tranamison electron micrograph of HIV particles. The central purple areas are RUA, which are surrounded by a protln cot (yellow) 100), How does HIV cause disease? HV targets a typeof white blood cell known a8 aT helper cell of CDt+ T eal (ee Box 1). T helper ces express 2 receptor on thee cell surface membrane known as CDS The CDs receptor enables T helper cells to bind with other white blood calls and simulate the biochemical pathways involved in a noemal immune response T helper cells play an important part inthe immune espns. Tei functions include ‘activation of B cells resulting in andy production {= regulation of CD8> T els (eyotorc Telly which attack virus infected and amour cll Infection with HIV leas to a reduction inthe aumber of working CD4+ T cells If the pumber ofthese cel alls {oo low, the Immune system ofthe patknt willbe unable to respond normally to other pathogens, and acquired immunodeficiency sypatome (MIDS) will develop. Death i ‘usually due w the development of cancer, or infection with “other pathogens that oecirs a8 3 result of the ft of the patent’ immane system How does HIV infect white blood cell HIV virus partes bind to shite blood cells by means of 4 vital envelope protein called gp120. This glycoprotein Tecognisee the CDA receptors on the surface of T helper cell Finding of gpl20 tothe CDA receptor fines the virus particle inthe cortet positon relative to the cell membrane Thin enables it to interact with o-receptors such as CORS, a protein sith seven membrane spanning sections (see "igure 4). Once the viral envelope interacts with both the (CDs reepior and the CRS co-rceptor, can fase with the cll surface membrane ofthe hostel, and itl RNA it released into the host cll eytoplasm (ee Figure). Resistance to HIV infection Some people are resistant to Infection with HIV, despte boeing exposed tothe sinus theough sexual contact These September 203, 4. Structure ofthe CERS coreceptor 1 Ervoipe protein gp120 binds to CDA receptor fT helpe cal sufae membrane, Fnayme RNA wana gptz0 oy Thelper call rnetope proteins and CORS oveceptar 2 the ital envelope fre ith the el srface tothe epi = \ Figere Singing of IV to helper cell18 4 ee erer roe pear ane individuals have @ mutation in the gene coding forthe CRS co-receptor About 19¢ of the Caucasian population is homonygous for this mutation, This mutation is given the name CCRS delta}? alle and involves the deletion ‘of 32 ise palts from the DNA sequence. As a result the mutant CCRS co-recepior protein is missing the last three membrane-spanning sections, and so carinot fanction Thies why Homozygous indvkluas who have to copies of the CORS dea? alee cannot make functional CORS receptors These indivals ae resistant to HIV ~ they do tot become infected, even when exposed to the vitus on several occasions CRS delta32 and HIV/AIDS treatment The discovery ofa gene conferring resistance t HIV nection ‘opens up the possibility of using vatious novel echniques to ret or prevent HIV infections: Gene therapy involves he inwroduction ofa new gene tan individual. This procedure is most appropriate in treating condiions sich ay cystic fibrosis, in which a est fnconal poten is mising is easier to use gene therapy to introduce a missing protein than to eliminate a healthy alll, An effective treatment involving the CCRS deks32 allele would equie the eral CCRS genes to be absent fom the treated cells, This woud reader them unable co make functional CCRS co-receptrn, This could only be achieved by ransplanting stem cells homozygous for CCRS delta? into the fected indvidisl rome —_ eee machine f Stoo ncucing ood nnn u Dover ‘\ Figure 6. Aohereris How white blood call are removed from the donor's blood What are stem cells? Stem cells are undifferentiated cell that can give tse © several diferent types of differentiated cell Due to thee Special abit, stem cells have a great deal of potential fvmedical science (ee Boocica Sera Review Vo. 23, bloga eres eenNo. 4, pp. 22-25) Stem cells can be harvested from 3 roummber of sources including the developing embryo, ‘umbilical cord, and sone adult tissues, Curtenty, the ‘ost clinically useful adult stem cll ate haematopoietic stem celle (HSCs, s6¢ Hox I) wich are found inthe bone ‘marrow. HSCs have been used successfully i tanaplante for several years, particularly in the teatment of cancers of the blood such as leukaemia, How do stom cell transplants work? HHSC transplants usualy involve 2 healthy donor with a tise type that matches that ofthe patient. Sem cells can be eatrated dieely from the bone marrow ia a surge procedure, o ca be obtained from the blood. The second rethod fs now the most widely used. The donor is fist tweaed with granulocyte-clony stimulating factor, which causes 1SCst0-mave from bone marta ino thecitcalation, “Thestem cellsare then collected by a proces called apheresis (Gee Figure 6), The recipient usally undergoes a course of treatment before receiving the transplant. The treatment destroys the diseased white blood cell, inchading HSC, using hhemexheraps or itadiation, Donr HSCs are ten inected Jno the patien’ blood. The transplanted stem cells migrate to the bone marrow and begin to replicate, eventually {epopulating the blood with healthy white blood cells ecause the ne ells originate from the transplanted HSCs they contain genetic material from the donor rather than the patients owa DNA, Stem cell wansplants ean be hazatdous. During the proces, the patient doesnot hare a functioning immune stem and $0 is at risk of serious ines or death from ‘other infections. There is alo a high incidence of gra ‘ermushost disease, in which the tranoplaned cells beg tak the hos own body cell Duet thes risks, tem cll ‘tansplans are usally only’ considered in the weatment of if threatening conditions such as leukaemia tn theory, similar techniques could be used 10 creat patients infected with HIV. The donor would need to be homozygous for the CCRS delta? mutation. Following transplantation of donor ells into the HIV patient, the patient's T helper cells — which will now be derived from the transplanted stem cells — ill not expres Functional {ERS co-ecepors and $0 wile resistant to infection by the HIV virus cure for AIDS? Highly active antiretrovieal therapy (HAART) has greatly improved survival of patiems with HIV since its Introduction in 1996, but it does not cure the disease In 2000, a pioneering medical treatment took pace on 2 patient who had been infected with HIV mon than 10 yeare previously. The patient had been tented with HAART for Several years and showed no signs of illnesses associated wwth AIDS, Unrated wo his HIV states, he patient developed ate rnyeloll Fukaeria (ANA), which sa cancer of blood cells belonging the myeloid ine (ee Hox 1). Rape production September 203, ey DNVERT teratonal Vand ADS cha ghiraidesciencettm Uk stem call Feundasne wor akscorgresearhlindes tml of abnormal white blood cells Heads to their buk-up in bbone martow, which preveats the development of normal white blood cells. Teatment for AML i usually either ‘chemotherapy of stem cll transplantation. In this cae, stem cll transplant wae deemed ¢o be the appropriste {weatment. The selected donor had a matching tie spe to minimise the chances of rejection, “The donor was also screened to ensure homozygosity for the CORS delta32 allele 30 that white blood cells produced from the grafted stem cells would noc express the CCRS co-tecepor, thus rendering them reitant to infection with HIN, The leukaemia returned anda second ransplant from the same donor was vequired 7 months later, but since then the patient has shown no further relapses, Despite the discontinuation of HAART treatment, {hee has also been no evidence of active replicating HIV Jn thispatent. This finding sggess thatthe patients newt ‘white blood cell remain resistant infection by HIV, and the traneplant has effectively provided along tem eure for the condition Stem cell transplants and HIV Although this case shows that stm cell rasplants can be ‘sed succesfully in the treatment of HIV, there ate several reasons why ths therapy 1s not widespread in its use. So fa, the therapy has only been tried on one patient Tis is because i is only ethical to perform stem cell wansplants fon patients with lifechreateing conditions such as AMI and she nurnber of HIV patients developing suck conditions {sextremely lw In addition, the chance of finding donors ‘eth sie ies matching the prospective patient atid 380 slemonstatng homozygosity for the CCRS deia3? allele islow. Until more sadies show thot stem cll trangplants can prevent HIV disease progression, ic is unlikely that 2 more ‘widespread clinical trial vill be authoried. Iven then ‘e may sil be consered too risky for HIV patents to be routinely offered sem cell transplants as a teetment ‘option, pariculaly given the success ofthe current HAART regime. Hovever ths cae as reinforced the importance of the CRS coreceptor in disease progression of AIDS, and encourages further development of antxetrovial eaten targeting this membrane protein. Veronica Mitchel has a degre in mei a renner