Hepatitis C Working towards a treatment ‘Viruses such as hepatitis C rely on the cells of their host in order to replicate, ‘Some do not harm the host, but some cause disease, Understanding viruses and how they work is an important first step in combating viral diseases, and modern genetic approaches are helping scientists do this a Key words Hepat Cvs CVI Liver cee ‘Genetic ersty Phylogenet te epatis © views (HCV) causes chronic inflammation ofthe liver in humans. This can lad 10 cithosis (ating) and even Cancer of the liver (ee Figure 1). HCV osesseris health sues workwide and yet many specs ofits function ave ail a mystery, We do not know hove the virge gets into cell, but once the virus is inside, neve copies of is genetic material are made using the host eels machinery. Viral proteins are hen synthesised in the cytoplasm The wtal DNA and proteins are packaged nto new virus particles tha eave the cell nd goon ta infect other ells Figure 1 The Sve from a patient suffering fom chasis. Cosi ofthe the liver in which lve tissue i teplaced with connective tisue, resulting in 26 Some people infected with HCVhave an immune system that fs ale to clear the virus — they ace TV for only a few weeks. Most people, however, develop a ifelong infection. After mans years. the liver becomes so diteased that i ean no longer function and without a liver transplant the patent will de Unfortunately, a transplanted liver ill became reinected within inte ofthe transpla, meaning that, without an effective treatment, ‘wansplan is enly a short-term solution. How is HCV transmitted? The Word Health Organization estimates that aboxt 2% of people worlwide are chronically infected swith HHCY. We cannot be completely aure of this number because many people do not know that they ate infeed, since ican ake years a develop symptoms of disease HCV transmission requires blood-to-blood contact. Today, it is mainly cansmitied via Inteaenous druguse or medical procedure. In some «countries (eg Japan) blood used fr rasfasions was Contaminated before the virus was first iene land many people became infected. In Fgypt HCV was spread through contaminated needles when eopleveere gen preventative eatment for another pathogen, Schitisoma. Currently people who inject ‘rag with contaminated needles are mot a ine Tes not clear how HCN ves spread in the past Ik may have been transmitted by a vector, sich a8 mosquitoes. This haw other inuses similar © HY, such as West Nile virus and dengue virus, are transmitted but there i litle evidence that HOV is eully spread in this way. The virus may also be !mainained atl levlsin the population by sexual ‘ormaternal transmission, hough boty are relatively Inefficient at uansmision of the vias compared ‘with blood to-hlond contactNot all HCV viruses are the same ang viruses mutate rapidly and so ae constantly changing, HCV is no exception. Iehas avery short {genome, only 10000 nucleotides kong compared ‘with 3 billion in the human genome. When Jhuman DNA is rephested, mistakes sometimes ‘occut, However, human cells havea proofreading” ‘mechanism o corte any mistakes, s0 the new DNA doesnot usually difer fom the origina. Therefore ‘pot many mutations accumulate overtime ike many wirates, HCV has no proofreading ‘mechanism, As te viru replicates in the host cll any incorrect nucleotides incorporated into the new fenome ate rained, HCV also has a very high ‘eplcation rate— millions of ew copies of the virus ae preuced and released from infected cells within Fou. Tete to factors est nthe accumulation ‘of many mitations ove a brie period of time, We ‘often think of mutations as being harm, but in a ‘rus they can be advantageous, because they alle it to evade the host immune response. Changes ‘accumulate n exons ofthe genome that immune cells are programmed to recognise. This means that the immune cells na longer Meni the virus aan invader. Genetic diversity The genome of HCY samples taken from infected people in diferent parts ofthe work an differ by September 203, eae ee Endemic A disease that has been in he papuson fr long enough that 236 lel hos ben reached Epidemic Anes tht roping, “Genetic diversity The vraton in genome sequences between inva the sere ree Specs. Genome The entre aalague of huey ermatian coded a INA or sme vases NA ‘Genotype The genetic make-up of an erganism Mutation Misles nthe genome made dung repation, Can be eter conc Ahan, sl) or etaned fn vise. Pathogen Amiroorenim that canes diesen thebot hati ec Prylogeneics Amethod Dat can conser the any we’ fay organs bsad an smarts ana aferences nthe genome eetor fn ergansm that wars apahogen rom one ost to arse. ‘pw 306% In ther words three out of every ten nucleotides ate differs. This isan enormous amount of genetic diversity fora single species. In contrat the Aiffeence between the DNA sequences ofndividual humans i es than 1% tnd between humans and chimpanzees itis tess than 59% Despite this divers, all the different strains of HCV cause the same basic liver disease The high genetic diversity an fast mutation rate make i dificult o develop an effective vaccine for hepatitis. Thi isbecase vaccines target specific components of 3 virus, sch 3 the outer protein coat, and i thie changes, the immune response that develops following vaccination m0 longer veers. ‘The influenza virus lysates this problem well You need anew fh jab ‘every year berause the virus mutates very quichly and last years vacine snot tffective against this yea’ strain ofl, Unfortunately there is no vaccine a al for HCV, although scientists are working on developing ove. For along time, the only treatments available were drug that boosted the immune system to fight off the infection. In the past ee years, however, drage that direct target the vtus are proving tobe mach more ffetve, and many-ae in development HCV genotypes HCV can be divided into diferent genotypes based on the differences between their genetic sequences. Thee are seven main genotypes: C1-C7. Although they all cause chronic infection and lier disease they alo show some dferences. Diflerent HCV genotypes are found in dferet geographical teas (se Figure 2. Cl sound in Aficaas well asin Europe the USA and Japan. However Gin Afrcas endemic while Gi in Europeand the ISA i eidemle. Endemic means that the number of people withthe virus remains steady in the population becatte the tansmnision ofthe diese i fay constant, G2 and Ga in Africa tnd G3 and G6 in Asa ae also endemic \Weknow thatepideic Gt in Europe and the USA and G4 in Egypt musthave tered theve pce fay een, because these genctypesshowed exponential [vt of new viral infections in these locations during the twentieth century. HCV genotypes are thought o ave moved around the world aver the centuries 2s humans migrated from one place to another. For example, G2 was probably ‘nerdiced into the Caribbean from west Ais hy human ransporation during the lave trade (GI is the most common HHCY genotype in the UK and i isthe hardest enotype to treat sith available drugs — ony about 50% of GL-infeted pecple se tated sucessfully. G2 and G3 ave ease 1 eat, wi 2 sucess ate of| Sound 809% 27‘ietbition worl nap shows where eV genotypes are mi found. For tampl, 0 genotypes other thn | Europe but the majo lott overiap in ia How old is HCV in humans? Iecause the HCY virus accumulates mutations so fast we can use mathematical techniques t0 trace its history by examining the similarities and Aiffeences in genome sequences ofthe diferent strains. This method is called phylogenetics. Ie is similar to making a family ee (ce Box I) Using these reconstructed vial family tees, we can date ‘he origin ofeach genotypebased on out knowlege ‘ofthe fate at which the wrus accumulates changes nis genome. Wis believed that each of the different endemic genotypes is 200-500 yeas old. All HCY genotypes Probably share a common ancestor Ne eanot say when oF where that ancestor existed but i fay certain thatthe orignal HCV ancestor occured in Fhumansa log time ag. ped gue A shows the eltonship between he rere genomes of HE. The nth of each re reflect the uber of rations nig to cch genotype The Hs, of re re regres he mesure seq rm arent ia Spl theres ofthe eels 2 edition of HC eae in ‘he past fay lng brand eis to each ofthe gency, meaing thatthe ae sao genetic ‘ference hom Figure A Phylogenetic wee omen’ 28 We still donot know whete HCV originally came from. Other viruses were frst transmitted to burmans from animals. For example, HIV (eee pp. 15-19) was probably transmitted to humans following cantct with an infected chimpanzee in ‘west Aiea. Howeeer, humans at the only specs ‘we know of tha can be infected with HCV. Other animal species nay be infected with a viussimar to HCY but we have not found i yet. also possible that other primates used 10 be infected ‘with avira similar to HCY, bat they weve able to czadicte i while humans were not This iil ‘unsolved mystery ‘What is the future? ‘This isan exciting ime in HCY research because -many promising new drugs ae Being ested. These ‘rugs may be ale to enacate the vis from people ‘who were previously dificult reat, suchas those infected with Gi, people also infected th HIN AIDS, and people who were given drugsthatdid not work The new drugs are dieceactng anvils — ‘they target viral enzymesto prevent the completion fof the viral life cele, whereas older drugs merely ‘boosted the patients immune stem. “The genetiifferences among the vil genorypes ‘ould play role in how ec one respons to drag therapy. We cam use ths information to develop drugs that target all genotypes, not just a Fee Furthermore, a8 the vitus changes overtime, it can develop mutations thot ate resistant toa drug. By studying these mutations, we gin valuable information about how the drugs work so that we can make more effective ones ‘The fight between pathogens and humans is ‘often compared to an ‘evolutionary arms race in ‘hich each opponent makes small improvements bloga eres eenin reponse to the other. We should be encouraged ‘ha the sefentats and doctors who ae Fighting HCY ate on thei way co winning the bate for good hopfully Points for discussion ' Scientists think that viruses arebeingtransmittd ftom animals to humans all the time. There ae probably many viruses that we dont even know bout that curently ive exclasiely in animals and {that could. make the “jump” into humans in the fare. What measies can take to avoid this happening? = Fora newly acquit virusto becomea problem, it has to evolve the ability to spread among humans, which does not seem to happen often Recently, researchers performed experiments in which they manipulated the influenza virus the ee ay The Enoopeds of Lie’ defiationo vin: tpaleoLarginfls ‘The Wel Heath Organization provides fermen on HeV! wontinyr comes {vottin ara phlognetis re revered ely at worn sinyurlcomie)see laboratory to make i transmissible among ferets (Ghought to resemble humans when i comes 19 fly tansmission). These experiments wortied some scientists and government with saggestions that these types of experiments should not be llwed. What are the pro and cons of performing such experiments? oe mente * Hcp Cv HCV) ecb infects 3% of he wes poplin + HEV warumision requits band 1 bled eat + HEV coves og losing ifcton rest peopl and thee fsa completely ec vestrert, Inlet people evel avr ver ses + HOV genetically dese od ferent types of HCV ar feud rend the wor * Pylogenstis peu to rae the org and evluton of HCV. + Undertanding the gents of vine wl pct t develop more ecve veer my revisiOn notes > Manage your own reision wth sep-y-spsunpor ‘rom exes Mike Boyle cc Frank Socheck! > Use specific case studies to mora yourknowiesye ‘of bdo! processes ana tne, >» Raise your grades by appjing clei te scoured wih theo of deetons ava kay words > Improve your skulle totacie specie exam quastons ‘Quick gulzes » www. therevisienbutton.co.uk/ ‘myrevisionnotes September 2013 Creer my revision nies as BIOLOGy Imyrevatn ot as BIOLOGY j amp | ese