"HEPATITIS C VIRUSHEPATITIS C VIRUSHepatitis C Virus, a causative agent for non A and non B hepatitis identified in the year 1989.1, 2 HCV is RNA virus belonging to the genus Hepacivirus in the Flaviviridae family .Flaviviridae family has 3 genera Hepacivirus, Pestivirus and Flavivirus (Table 1). HCVexhibit differences when compared to other members of the family. Flavivirus translation is3 cap dependent , whereas HCV translation is cap independent and mediated by the internalribosome entry site. The 3’untranslated region (UTR) in flavivirus is highly structured, on theother hand the HCV 3’UTR is short and less structured. HCV is transmitted by direct bloodto blood contacts whereas flaviviruses are transmitted by mosquitoes and tics. HCVinfections often progress to chronic state due to failed immune response whereas a strong andadapted humoral and cellular immune response resolves infections in flavivirus and pestivirusinfections. Table 1- The family of FlaviviridaeFamily Genera MembersFlaviviridae Hepacivirus HCVTamarin virusGB virus BPestivirus Diarrhea virusClassical swine fever virusBorder disease virusFlavivirus Yellow fever virusDengue fever virusJapanese encephalitis virusTick borne encephalitis virus HCV is a small (55 to 65nm), spherical, enveloped, hepatotropic RNA virus that cause acuteand chronic hepatitis in humans.Following initial infection 80% of the people do notdevelop any symptoms. However the symptoms mainly include fever, fatigue, decreasedappetite, nausea, vomiting, abdominal pain, dark urine, grey-coloured faeces, joint pain andjaundice. Raised ALT and AST levels persist for years. The infection is defined as chronicafter six months of the persistence of the viral RNA in the blood stream. If infection persistsin the patient, it leads to cirrhosis and hepatocellular carcinoma.HCV is a bloodborne virus and the most common modes of transmission are -1. Inadequate sterilisation of medical equipment2. Transfusion of unscreened blood and blood products3. Unsafe injection practices 4. Hetero or homo sexual practises, having sexual partners who are HCV infectedGEOGRAPHIC DISTRIBUTION HCV virus is classified into 7 genotypes (1-7) and many subunits based on the nucleotidesequence of the core/E1 and NS5B regions (smith DB et al Hepatology 2014). HCV exhibits4 a high degree of genetic diversity with 7 recognised genotypes . Genotype 1 is distributedworldwide with more Prevelance in America, Europe, Japan and Asia. Genotype 2 isdistributed in South America and East Asia. Genotype 3 is prevalent in Europe, UnitedStates, Australia and southern Asia. Africa and Middle East show genotype 4 as a commongenotype. Genotype 5 is seen in South Africa, Middle East and India. Genotype 6 is seen inSouth East Asia. There is only one report of Genotype 7 isolated from Canada from anCentral African Immigrant. HCV GENOME ORGANISATIONHCV is a positive sense single stranded RNA virus with approximately 9600 nucleotides.HCV genome has one continuous open reading frame (ORF) flanked by untranslated regions(UTR) at 5’ and 3’ regions termed as 5’ UTR and 3’ UTR respectively. The open readingframe encodes the structural (Core and Envelop proteins) and the non structural (NS3, NS4A,NS4B, NS5A and NS5B) components of the HCV( Figure 1). Figure 1. HCV genome Organisation - Schematic of HCV genome organization showingthe position ofHCV genes and proposed functions of gene products. 5’ and 3’ UTR areindicated as shown. The Numbering refers to nucleotide positions of genes, based on thesequence of HCV genotype.The components of HCV genome are discussed below-? 5’UTR :The HCV 5’ UTR is a 341 nucleotide region located upstream of the coding region. It has 45, 6domains (I-IV) with numerous stem loops . The domains II to IV along with the first 12- 307 nucleotides of the core form the Internal Ribosome Entry Site (IRES) .The IRES region binds to the 40S ribosomal region and initiates the translation.? 3’UTR :The 3’ UTR has approximately 225 nucleotides and has three regions – 1. A variable region of 40 nucleotides2. A long poly(U)- poly (U/UC) tract3. Highly conserved 3’ terminal stretch of 98 nt( X’ region) that include 3 stem loopstructures (SL1, SL2 and SL3)? Core protein :HCV core is the viral nucleocapsid protein involved in different activities like viral capsidformation, RNA binding, nuclear localisation, association with the endoplasmic reticulum8 and lipid droplets . It has pro and anti apoptotic functions, stimulates hepatocytes growth in9-11 Huh 7 cells by transcriptional regulation of growth related genes .? Envelop proteins :E1 and E2 are the two envelop proteins that surround the virus mediating the viral entry andfusion. E1 and E2 have molecular weights of 33-35 and 70-72 kDa respectively. E1 and E212, 13 are highly glycosylated with 5 and 11 glycosylation sites respectively . The glycosylationis important as it helps in envelop glycoprotein folding and formation of E1E2 complexes,13, 14 receptor interactions with virus and antigenic variation . The hypervariable region (HVR)present in E2 has amino acid sequence differing up to 80% between different HCV isolates.HVR1 is positively charged and play a role in host cell recognition and attachment by15 interacting with the negatively charged residues on the cell surface . The cell surfacereceptors SRB1 and CD81 bind to HCV E2 via the HVR1 region. The different vaccineinitiatives in clinical trial have focused on inducing neutralising antibodies against the E1E2regions. ? P7 protein : P7 is a membrane spanning 63 amino acid polypeptide located between HCV E2 and NS2genes. The cleavage of P7 is mediated by ER signal peptidases of the host cell. P7 proteins16 form ion channels that play an essential role in virus infection and are similar to viroporins .17 P7 is essential for assembly of virus particle and release of infectious virions .? NS2 :NS2 protein is a 21-23 kDa transmembrane protein essential for completion of viralreplication cycle. The C terminal part of the NS2 along with the N terminal domain of theNS3 forms the NS2/NS3 autoprotease. The domain required for cleavage is mapped between18 827 and 1207 of the polyprotein .? NS3 protein :NS3 is a 67 kDa protein with N terminal Serine protease activity and C terminal NTPase/19 Helicase activity . The three amino acid residues His 1083, Asp 1107 and Ser 1165 areresponsible for the protein catalytic activity.NS3 is known to interact with Protein Kinase A(PKA), and deregulate the intracellular signalling by preventing the catalytic subunit of PKA20 to enter into the nucleus . It is also known to inhibit the RIG 1 and TLR3 signalling as a host21 defence mechanism .? NS4A protein:NS4A is a 54 amino acid protein which acts as a cofactor for NS3 protein. The N terminus is22 highly hydrophobic and targets NS3 to the ER membrane . The interaction between NS3 andC terminus of NS4A cause activation of the NS3 active site and more efficient protease23 24 cleavage . It is also required for NS5A phosphorylation .? NS4B protein :NS4B is a 27 kDa protein and is involved in recruiting other viral proteins. It is involved information of membranous web, an area where all viral proteins are localized and a replication25, 26 complex is formed . ? NS5A protein:NS5A is a 56-58 kDa phosphorylated zinc metalloprotein that is involved in virus replicationand regulation of cellular pathways by binding to viral RNA and various host factors. The Nterminal regions contain amphipathic alpha helix and is necessary for membrane localisationin perinuclear membranes and for replication complex assembly. NS5A contain region calledInterferon alpha sensitivity determining region (ISDR) that confers the virus resistant to27, 28 interferon by binding to the IFN alpha stimulated gene product PKR protein kinase .? NS5B protein :NS5B a RNA dependent RNA polymerase is a tail anchored protein of 65kDa in size whichcatalyses the viral replication. It has a right hand polymerase shape with finger, palm and29 thumb sub domains . Replication occurs via the synthesis of minus-strand RNA intermediateusing the genome as template followed by synthesis of plus- strand RNA which translates togive the viral polyprotein. "