Examine individual changes

'{{about|the viral particle|the disease|Hepatitis C}} {{Taxobox | name = Hepatitis C virus | image = hCV EM picture 2.png | image_width = 250px | image_caption = [[Electron micrograph]] of hepatitis C virus purified from cell culture. Scale: black bar&nbsp;= 50&nbsp;[[nanometre]]s | virus_group = iv | ordo = ''Unassigned'' | familia = ''[[Flaviviridae]]'' | genus = ''[[Hepacivirus]]'' | species = '''''Hepacivirus C''''' }} '''Hepatitis C virus''' ('''HCV''') is a small (55–65 [[Nanometre|nm]] in size), [[viral envelope|enveloped]], [[Sense (molecular biology)#Positive-sense|positive-sense]] single-stranded [[RNA virus]] of the family ''[[Flaviviridae]]''. Hepatitis C virus is the cause of [[hepatitis C]] and some cancers such as liver cancer ([[hepatocellular carcinoma]], abbreviated HCC) and [[lymphoma]]s in humans.<ref name="Ferri2015">{{cite journal|last1=Ferri|first1=Clodoveo|title=HCV syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin’s lymphoma, and cancer|journal=World Journal of Hepatology|volume=7|issue=3|year=2015|pages=327|issn=1948-5182|doi=10.4254/wjh.v7.i3.327}}</ref><ref>{{cite journal |pmid=23871966 | doi=10.1016/j.canlet.2013.06.028 | volume=345 | title=Mechanisms of HCV-induced liver cancer: what did we learn from in vitro and animal studies? | pmc=3844040 | year=2014 | journal=Cancer Lett. | pages=210–5 |vauthors=Rusyn I, Lemon SM }}</ref> ==Taxonomy== The hepatitis C virus belongs to the genus, blah blah blah. it is just a sin that is in the world from adam and eve doing the wrong thing ''[[Hepacivirus]]'', a member of the family ''[[Flaviviridae]]''. Until recently it was considered to be the only member of this genus. However a member of this genus has been discovered in [[dog]]s: [[canine hepacivirus]].<ref name=Kapoor2011>{{cite journal | author = Kapoor A, Simmonds P, Gerold G, Qaisar N, Jain K, Henriquez JA, Firth C, Hirschberg DL, Rice CM | year = 2011 | title = Characterization of a canine homolog of hepatitis C virus | journal = Proc Natl Acad Sci U S A | volume = 108 | issue = 28| pages = 11608–13 |bibcode = 2011PNAS..10811608K |doi = 10.1073/pnas.1101794108 | pmid = 21610165 | pmc = 3136326 | author2 = and others | displayauthors = 1 | last3 = Gerold | last4 = Qaisar | last5 = Jain | last6 = Henriquez | last7 = Firth | last8 = Hirschberg | last9 = Rice | last10 = Shields | last11 = Lipkin }}</ref> There is also at least one virus in this genus that infects horses.<ref name=Burbelo2012>{{cite journal |vauthors=Burbelo PD, Dubovi EJ, Simmonds P, etal |title=Serology-enabled discovery of genetically diverse hepaciviruses in a new host |journal=J. Virol. |volume=86 |issue=11 |pages=6171–8 |date=June 2012 |pmid=22491452 |pmc=3372197 |doi=10.1128/JVI.00250-12 |url=http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=22491452 }}</ref> Several additional viruses in the genus have been described in bats and rodents.<ref name=Quan2013>{{cite journal |vauthors=Quan PL, Firth C, Conte JM, etal |title=Bats are a major natural reservoir for hepaciviruses and pegiviruses |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=110 |issue=20 |pages=8194–9 |date=May 2013 |pmid=23610427 |pmc=3657805 |doi=10.1073/pnas.1303037110 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=23610427 |bibcode=2013PNAS..110.8194Q }}</ref><ref name=Kapoor2013>{{cite journal |vauthors=Kapoor A, Simmonds P, Scheel TK, etal |title=Identification of rodent homologs of hepatitis C virus and pegiviruses |journal=MBio |volume=4 |issue=2 |pages=e00216–13 |year=2013 |pmid=23572554 |pmc=3622934 |doi=10.1128/mBio.00216-13 |url=http://mbio.asm.org/cgi/pmidlookup?view=long&pmid=23572554 }}</ref> ==Structure== [[Image:HCV structure.png|left|thumb|Simplified diagram of the structure of the Hepatitis C virus particle]] The hepatitis C virus particle consists of a lipid membrane envelope that is 55 to 65 nm in diameter.<ref name=":1">{{Cite journal|last=Dubuisson|first=Jean|last2=Cosset|first2=François-Loïc|date=2014|title=Virology and cell biology of the hepatitis C virus life cycle – An update|url=https://doi.org/10.1016/j.jhep.2014.06.031|journal=Journal of Hepatology|volume=61|issue=1|pages=S3-S13|via=Science Direct}}</ref><ref name=":2">{{Cite journal|last=Kaito|first=Masahiko|last2=Ishida|first2=Satoshi|last3=Tanaka|first3=Hideaki|last4=Horiike|first4=Shinichiro|last5=Fujita|first5=Naoki|last6=Adachi|first6=Yukihiko|last7=Kohara|first7=Michinori|last8=Konishi|first8=Masayoshi|last9=Watanabe|first9=Shozo|title=Morphology of hepatitis C and hepatitis B virus particles as detected by immunogold electron microscopy|url=https://link.springer.com/article/10.1007/s00795-006-0317-8#citeas|journal=Medical Molecular Morphology|language=en|volume=39|issue=2|doi=10.1007/s00795-006-0317-8#citeas|issn=1860-1480}}</ref> Two viral envelope [[glycoprotein]]s, E1 and E2, are embedded in the lipid envelope.<ref name="pmid12820185">{{cite journal|author=Op De Beeck A, Dubuisson J|last2=Dubuisson|year=2003|title=Topology of hepatitis C virus envelope glycoproteins|journal=Rev. Med. Virol.|volume=13|issue=4|pages=233–41|doi=10.1002/rmv.391|pmid=12820185}}</ref> They take part in viral attachment and entry into the cell.<ref name=":1" /> Within the envelope is an icosahedral core that is 33 to 40 nm in diameter.<ref name=":2" /> Inside the core is the RNA material of the virus.<ref name=":1" /> === E1 and E2 Glycoproteins === E1 and E2 are covalently bonded when embedded in the envelope of HCV and are stabilized by disulfide bonds. E2 is globular and seems to protrude 6 nm out from the envelope membrane according to electron microscope images.<ref name=":2" /> These glycoproteins play an important role in the interactions hepatitis C has with the immune system. The hypervariable region 1 (HVR1) can be found on the E2 glycoprotein.<ref name=":1" /> HVR1 is flexible and quite accessible to surrounding molecules.<ref name=":3">{{Cite journal|last=Castelli|first=Matteo|last2=Clementi|first2=Nicola|last3=Pfaff|first3=Jennifer|last4=Sautto|first4=Giuseppe A.|last5=Diotti|first5=Roberta A.|last6=Burioni|first6=Roberto|last7=Doranz|first7=Benjamin J.|last8=Dal Peraro|first8=Matteo|last9=Clementi|first9=Massimo|date=2017-03-16|title=A Biologically-validated HCV E1E2 Heterodimer Structural Model|url=https://www.nature.com/articles/s41598-017-00320-7|journal=Scientific Reports|language=En|volume=7|issue=1|doi=10.1038/s41598-017-00320-7|issn=2045-2322}}</ref> HVR1 helps E2 shield the virus from the immune system. It prevents CD81 from latching onto its respective receptor on the virus.<ref name=":3" /> In addition, E2 can shield E1 from the immune system.<ref name=":3" /> Although HVR1 is quite variable in amino acid sequence, this region has similar chemical, physical, and conformational characteristics across many E2 glycoproteins.<ref>{{Cite journal|last=Basu|first=Arnab|last2=Beyene|first2=Aster|last3=Meyer|first3=Keith|last4=Ray|first4=Ranjit|date=May 2004|title=The Hypervariable Region 1 of the E2 Glycoprotein of Hepatitis C Virus Binds to Glycosaminoglycans, but This Binding Does Not Lead to Infection in a Pseudotype System|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC387685/|journal=Journal of Virology|volume=78|issue=9|pages=4478–4486|doi=10.1128/JVI.78.9.4478-4486.2004|issn=0022-538X|pmid=15078928|via=}}</ref> ==Genome== [[Image:HCV genome.png|right|thumb|300px|Genome organisation of Hepatitis C virus]] Hepatitis C virus has a positive sense single-stranded [[RNA]] [[genome]]. The genome consists of a single [[open reading frame]] that is 9600 [[nucleotide]] bases long.<ref name="pmid11252351">{{cite journal |author=Kato N |title=Genome of human hepatitis C virus (HCV): gene organization, sequence diversity, and variation |journal=Microb. Comp. Genom. |volume=5 |issue=3 |pages=129–51 |year=2000 |pmid=11252351 |doi=10.1089/mcg.2000.5.129}}</ref> This single open reading frame is translated to produce a single protein product, which is then further processed to produce smaller active proteins. This is why on publicly available databases, such as the European Bioinformatic Institute, the viral proteome only consists of 2 proteins. At the 5' and 3' ends of the RNA are the [[Untranslated region|UTR]], that are not translated into proteins but are important to translation and replication of the viral RNA. The 5' UTR has a [[ribosome]] binding site<ref name="pmid11497352">{{cite journal |author=Jubin R |title=Hepatitis C IRES: translating translation into a therapeutic target |journal=Curr. Opin. Mol. Ther. |volume=3 |issue=3 |pages=278–87 |year=2001 |pmid=11497352 }}</ref> or [[Internal ribosome entry site|internal ribosome entry site (IRES)]] that initiates the translation of a very long protein containing about 3,000 amino acids. The core domain of the [[Hepatitis C virus internal ribosome entry site|HCV IRES]] contains a four-way helical junction that is integrated within a predicted [[pseudoknot]].<ref name=Berry2011>{{cite journal |author=Berry KE, Waghray S, Mortimer SA, Bai Y, Doudna JA |title=Crystal structure of the HCV IRES central domain reveals strategy for start-codon positioning |journal=Structure |volume=19 |issue=10 |pages=1456–66 |date=October 2011 |pmid=22000514 |doi=10.1016/j.str.2011.08.002 |url=http://linkinghub.elsevier.com/retrieve/pii/S0969-2126(11)00280-2 |pmc=3209822|last2=Waghray |last3=Mortimer |last4=Bai |last5=Doudna }}</ref> The conformation of this core domain constrains the open reading frame's orientation for positioning on the 40S ribosomal subunit. The large pre-protein is later cleaved by cellular and viral [[protease]]s into the 10 smaller proteins that allow viral replication within the host cell, or assemble into the mature viral particles.<ref name="pmid17552023">{{cite journal |author=Dubuisson J |title=Hepatitis C virus proteins |journal=World J. Gastroenterol. |volume=13 |issue=17 |pages=2406–15 |year=2007 |pmid=17552023 |pmc=4146758 |doi=10.3748/wjg.v13.i17.2406}}</ref> Structural proteins made by the hepatitis C virus include Core protein, [[E1 (HCV)|E1]] and [[E2 (HCV)|E2]]; nonstructural proteins include [[NS2 (HCV)|NS2]], [[NS3 (HCV)|NS3]], [[NS4A]], [[NS4B]], [[NS5A]], and [[NS5B]].{{citation needed|date=May 2016}} ==Molecular biology== [[File:HCV.png|thumb|HCV]] {{Refimprove section|date=May 2016}} The proteins of this virus are arranged along the genome in the following order: N terminal-core-envelope (E1)–E2–p7-nonstructural protein 2 (NS2)–NS3–NS4A–NS4B–NS5A–NS5B–C terminal. The mature nonstructural proteins (NS2 to NS5B) generation relies on the activity of viral proteinases.<ref name=DeFrancesco1999>{{cite journal | author = De Francesco R | year = 1999 | title = Molecular virology of the hepatitis C virus | journal = J Hepatol | volume = 31 | issue = Suppl 1| pages = 47–53 | doi = 10.1016/S0168-8278(99)80374-2 | pmid = 10622560 }}</ref> The NS2/NS3 junction is cleaved by a metal dependent autocatalytic proteinase encoded within NS2 and the N-terminus of NS3. The remaining cleavages downstream from this site are catalysed by a serine proteinase also contained within the N-terminal region of NS3. The core protein has 191 amino acids and can be divided into three domains on the basis of hydrophobicity: domain 1 (residues 1–117) contains mainly basic residues with two short hydrophobic regions; domain 2 (residues 118–174) is less basic and more hydrophobic and its C-terminus is at the end of p21; domain 3 (residues 175–191) is highly hydrophobic and acts as a signal sequence for E1 envelope protein. Both envelope proteins (E1 and E2) are highly glycosylated and important in cell entry. E1 serves as the fusogenic subunit and E2 acts as the receptor binding protein. E1 has 4–5 N-linked glycans and E2 has 11 N-glycosylation sites. The p7 protein is dispensable for viral genome replication but plays a critical role in virus morphogenesis. This protein is a 63 amino acid membrane spanning protein which locates itself in the endoplasmic reticulum. Cleavage of p7 is mediated by the endoplasmic reticulum's signal peptidases. Two transmembrane domains of p7 are connected by a cytoplasmic loop and are oriented towards the endoplasmic reticulum's lumen. NS2 protein is a 21–23 [[kiloDalton]] (kDa) transmembrane protein with protease activity. NS3 is 67 kDa protein whose N-terminal has serine protease activity and whose C-terminal has NTPase/helicase activity. It is located within the endoplasmic reticulum and forms a heterodimeric complex with NS4A—a 54 amino acid membrane protein that acts as a cofactor of the proteinase. NS4B is a small (27 kDa) hydrophobic integral membrane protein with 4 transmembrane domains. It is located within the endoplasmic reticulum and plays an important role for recruitment of other viral proteins. It induces morphological changes to the endoplasmic reticulum forming a structure termed the membranous web. NS5A is a hydrophilic phosphoprotein which plays an important role in viral replication, modulation of cell signaling pathways and the interferon response. It is known to bind to endoplasmic reticulum anchored human VAP proteins.<ref name=Gupta2012>{{cite journal |author=Gupta G, Qin H, Song J |title=Intrinsically unstructured domain 3 of hepatitis C Virus NS5A forms a "fuzzy complex" with VAPB-MSP domain which carries ALS-causing mutations |journal=PLoS ONE |volume=7 |issue=6 |pages=e39261 |year=2012 |pmid=22720086 |pmc=3374797 |doi=10.1371/journal.pone.0039261 |url=http://dx.plos.org/10.1371/journal.pone.0039261|last2=Qin |last3=Song |bibcode=2012PLoSO...739261G }}</ref> The NS5B protein (65 kDa) is the viral RNA dependent [[RNA polymerase]]. NS5B has the key function of replicating the HCV’s viral RNA by using the viral positive RNA strand as its template and catalyzes the polymerization of ribonucleoside triphosphates (rNTP) during RNA replication.<ref>{{Cite journal | pmid = 22303022| pmc = 3323022| year = 2012| author1 = Jin| first1 = Z| title = Assembly, purification, and pre-steady-state kinetic analysis of active RNA-dependent RNA polymerase elongation complex| journal = Journal of Biological Chemistry| volume = 287| issue = 13| pages = 10674–83| last2 = Leveque| first2 = V| last3 = Ma| first3 = H| last4 = Johnson| first4 = K. A.| last5 = Klumpp| first5 = K| doi = 10.1074/jbc.M111.325530}}</ref><ref>{{cite journal |author=Moradpour D, Penin F, Rice CM |title=Replication of hepatitis C virus |journal=Nat. Rev. Microbiol. |volume=5 |issue=6 |pages=453–63 |date=June 2007 |pmid=17487147 |doi=10.1038/nrmicro1645 |last2=Penin |last3=Rice }}</ref><ref>{{cite journal |vauthors=Rigat K, Wang Y, Hudyma TW, etal |title=Ligand-induced changes in hepatitis C virus NS5B polymerase structure |journal=Antiviral Res. |volume=88 |issue=2 |pages=197–206 |date=November 2010 |pmid=20813137 |doi=10.1016/j.antiviral.2010.08.014 |url=http://linkinghub.elsevier.com/retrieve/pii/S0166-3542(10)00701-1 }}</ref> Several crystal structures of NS5B polymerase in several crystalline forms have been determined based on the same consensus sequence BK (HCV-BK, genotype 1).<ref>{{cite journal |vauthors=Biswal BK, Cherney MM, Wang M, etal |title=Crystal structures of the RNA-dependent RNA polymerase genotype 2a of hepatitis C virus reveal two conformations and suggest mechanisms of inhibition by non-nucleoside inhibitors |journal=J. Biol. Chem. |volume=280 |issue=18 |pages=18202–10 |date=May 2005 |pmid=15746101 |doi=10.1074/jbc.M413410200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15746101 }}</ref> The structure can be represented by a right hand shape with fingers, palm, and thumb. The encircled active site, unique to NS5B, is contained within the palm structure of the protein. Recent studies on NS5B protein genotype 1b strain J4’s (HC-J4) structure indicate a presence of an active site where possible control of nucleotide binding occurs and initiation of de-novo RNA synthesis. De-novo adds necessary primers for initiation of RNA replication.<ref>{{cite journal |author=O'Farrell D, Trowbridge R, Rowlands D, Jäger J |title=Substrate complexes of hepatitis C virus RNA polymerase (HC-J4): structural evidence for nucleotide import and de-novo initiation |journal=J. Mol. Biol. |volume=326 |issue=4 |pages=1025–35 |date=February 2003 |pmid=12589751 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022283602014390 |doi=10.1016/s0022-2836(02)01439-0|last2=Trowbridge |last3=Rowlands |last4=Jäger }}</ref> Current research attempts to bind structures to this active site to alter its functionality in order to prevent further viral RNA replication.<ref>{{cite journal |vauthors=Biswal BK, Wang M, Cherney MM, etal |title=Non-nucleoside inhibitors binding to hepatitis C virus NS5B polymerase reveal a novel mechanism of inhibition |journal=J. Mol. Biol. |volume=361 |issue=1 |pages=33–45 |date=August 2006 |pmid=16828488 |doi=10.1016/j.jmb.2006.05.074 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-2836(06)00692-9 }}</ref> An 11th has also been described.<ref name=Walewski2001>{{cite journal | author = Walewski JL, Keller TR, Stump DD, Branch AD | year = 2001 | title = Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame | journal = RNA | volume = 7 | issue = 5| pages = 710–721 | doi = 10.1017/S1355838201010111 | pmid = 11350035 | pmc = 1370123 | last2 = Keller | last3 = Stump | last4 = Branch }}</ref><ref name=Baghbani-arani2012>{{cite journal |vauthors=Baghbani-arani F, Roohvand F, Aghasadeghi MR, Eidi A, Amini S, Motevalli F, Sadat SM, Memarnejadian A, Khalili G, etal | year = 2012 | title = Expression and characterization of Escherichia coli derived hepatitis C virus ARFP/F protein | journal = Mol Biol (Mosk) | volume = 46 | issue = 2| pages = 251–9 | doi = 10.1134/S0026893312020033 |pmid=22670521 }}</ref> This protein is encoded by a +1 [[frameshift]] in the capsid gene. It appears to be antigenic but its function is unknown. ==Replication== Replication of HCV involves several steps. The virus replicates mainly in the [[hepatocyte]]s of the [[liver]], where it is estimated that daily each infected cell produces approximately fifty virions (virus particles) with a calculated total of one trillion virions generated. The virus may also replicate in [[peripheral blood mononuclear cell]]s, potentially accounting for the high levels of [[Immunology|immunological disorder]]s found in chronically infected HCV patients. In the liver, the HCV particles are brought into the sinusoids by blood flow. These sinusoids neighbor hepatocyte cells.<ref name=":1" /> HCV is able to pass through the endothelium of the sinusoids and make its way to the basolateral surface of the hepatocyte cells.<ref name=":1" /> HCV has a wide variety of [[genotype]]s and mutates rapidly due to a high error rate on the part of the virus' [[RNA-dependent RNA polymerase]]. The mutation rate produces so many variants of the virus it is considered a [[Quasispecies model|quasispecies]] rather than a conventional virus species.<ref>{{cite journal |author=Bartenschlager R, Lohmann V |title=Replication of hepatitis C virus |journal=J. Gen. Virol. |volume=81 |issue=Pt 7 |pages=1631–48 |date=July 2000 |pmid=10859368 |url= http://vir.sgmjournals.org/cgi/content/full/81/7/1631|last2=Lohmann |doi=10.1099/0022-1317-81-7-1631}}</ref> Entry into host cells occur through complex interactions between virions, especially through their glycoproteins, and cell-surface molecules [[CD81]], [[LDL receptor]], [[SCARB1|SR-BI]], [[DC-SIGN]], [[CLDN1|Claudin-1]], and [[Occludin]].<ref>{{Cite journal| last2 = Barth| last4 = Baumert| last1 = Zeisel | first1 = M. | first2 = H. | first4 = T. | first3 = C.| last3 = Schuster| title = Hepatitis C virus entry: molecular mechanisms and targets for antiviral therapy| year = 2009| volume = 14| issue = 8| pmid = 19273272| bibcode = 2009CNSNS..14.3274H| pmc = 3235086| journal = Frontiers in Bioscience| doi = 10.1016/j.cnsns.2008.11.006| pages = 3274–3285}}</ref><ref>{{Cite journal| last1 = Kohaar | first1 = I.| last2 = Ploss | first2 = A.| last3 = Korol | first3 = E.| last4 = Mu | first4 = K.| last5 = Schoggins | first5 = J.| last6 = O'Brien | first6 = T.| last7 = Rice | first7 = C.| last8 = Prokunina-Olsson | first8 = L.| title = Splicing diversity of the human OCLN gene and its biological significance for hepatitis C virus entry| journal = Journal of Virology| volume = 84| issue = 14| pages = 6987–6994| year = 2010| pmid = 20463075| pmc = 2898237| doi = 10.1128/JVI.00196-10}}</ref> The envelope of HCV is similar to very-low density lipoproteins (VLDL) and low-density lipoproteins (LDL).<ref name=":1" /> Because of this similarity, the virus is thought to be able to associate with apolipoproteins. It could surround itself with lipoproteins, partially covering up E1 and E2. Recent research indicates that these apolipoproteins interact with scavenger receptor B1 (SR-B1). SR-B1 is able to remove lipids from the lipoproteins around the virus to better allow for HVR1 contact. Claudin 1, which is a tight-junction protein, and CD81 link to create a complex, priming them for later HCV infection processes. As immune system is triggered, macrophages increase the amount of TNF- α around the hepatocytes which are being infected. This triggers the migration of occludin, which is another tight-junction complex, to the basolateral membrane. The HCV particle is ready to enter the cell.<ref name=":1" /> These interactions lead to the endocytosis of the viral particle. This process is aided by clathrin proteins. Once inside an early endosome, the endosome and the viral envelope fuse and the RNA is allowed into the cytoplasm.<ref name=":1" />[[Image:HepC replication.png|right|thumb|300px|A simplified diagram of the HCV replication cycle]] HCV takes over portions of the intracellular machinery to replicate.<ref name="lindenbach">{{cite journal | author = Lindenbach B, Rice C | title = Unravelling hepatitis C virus replication from genome to function | journal = Nature | volume = 436 | issue = 7053 | pages = 933–8 | year = 2005 | pmid = 16107832 | doi = 10.1038/nature04077|bibcode = 2005Natur.436..933L | last2 = Rice }}</ref> The HCV genome is [[translation (biology)|translated]] to produce a single protein of around 3011 amino acids. The polyprotein is then proteolytically processed by viral and cellular [[proteases]] to produce three structural (virion-associated) and seven nonstructural (NS) proteins. Alternatively, a frameshift may occur in the Core region to produce an Alternate Reading Frame Protein (ARFP).<ref>{{Cite journal | last1 = Branch | first1 = A. D. | last2 = Stump | first2 = D. D. | last3 = Gutierrez | first3 = J. A. | last4 = Eng | first4 = F. | last5 = Walewski | first5 = J. L. | title = The Hepatitis C Virus Alternate Reading Frame (ARF) and Its Family of Novel Products: The Alternate Reading Frame Protein/F-Protein, the Double-Frameshift Protein, and Others | doi = 10.1055/s-2005-864786 | journal = Seminars in Liver Disease | volume = 25 | issue = 1 | pages = 105–117 | year = 2005 | pmid = 15732002 | pmc = }}</ref> HCV encodes two proteases, the NS2 [[cysteine]] autoprotease and the NS3-4A [[serine]] protease. The NS proteins then recruit the viral genome into an RNA replication complex, which is associated with rearranged cytoplasmic membranes. RNA replication takes places via the viral RNA-dependent [[RNA polymerase]] NS5B, which produces a negative strand RNA intermediate. The negative strand RNA then serves as a template for the production of new positive strand viral genomes. Nascent genomes can then be translated, further replicated or packaged within new virus particles. The virus replicates on intracellular [[lipid membrane]]s.<ref name=Dubuisson2002>{{cite journal | author = Dubuisson J, Penin F, Moradpour D | year = 2002 | title = Interaction of hepatitis C virus proteins with host cell membranes and lipids | journal = Trends Cell Biol | volume = 12 | issue = 11| pages = 517–523 | doi = 10.1016/S0962-8924(02)02383-8 | pmid = 12446113 | last2 = Penin | last3 = Moradpour }}</ref> The [[endoplasmic reticulum]] in particular are deformed into uniquely shaped membrane structures termed 'membranous webs'. These structures can be induced by sole expression of the viral protein NS4B.<ref name=Egger2002>{{cite journal | author = Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D, Bienz K | year = 2002 | title = Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex | journal = J Virol | volume = 76 | issue = 12| pages = 5974–84 | doi = 10.1128/JVI.76.12.5974-5984.2002 | pmid = 12021330 | pmc = 136238 | last2 = Wölk | last3 = Gosert | last4 = Bianchi | last5 = Blum | last6 = Moradpour | last7 = Bienz }}</ref> The core protein associates with lipid droplets and utilises [[microtubule]]s and [[dynein]]s to alter their location to a perinuclear distribution.<ref name=Boulant2008>{{cite journal | author = Boulant S, Douglas MW, Moody L, Budkowska A, Targett-Adams P, McLauchlan J | year = 2008 | title = Hepatitis C virus core protein induces lipid droplet redistribution in a microtubule- and dynein-dependent manner | journal = Traffic | volume = 9 | issue = 8| pages = 1268–82 | doi = 10.1111/j.1600-0854.2008.00767.x | pmid = 18489704 | last2 = Douglas | last3 = Moody | last4 = Budkowska | last5 = Targett-Adams | last6 = McLauchlan }}</ref> Release from the hepatocyte may involve the very low density [[Very low-density lipoprotein|lipoprotein]] secretory pathway.<ref name=Syed2010>{{cite journal | author = Syed GH, Amako Y, Siddiqui A | year = 2010 | title = Hepatitis C virus hijacks host lipid metabolism | journal = Trends Endocrinol Metab | volume = 21 | issue = 1| pages = 33–40 | doi = 10.1016/j.tem.2009.07.005 | pmid = 19854061 | pmc = 2818172 | last2 = Amako | last3 = Siddiqui }}</ref> Another hypothesis states that the viral particle may be secreted from the endoplasmic reticulum through the endosomal-sorting complex required for transport (ESCRT) pathway.<ref name=":1" /> This pathway is normally utilized to bud vesicles out of the cell. The only limitation to this hypothesis is that the pathway is normally used for cellular budding, and it is not known how HCV would commandeer the ESCRT pathway for use with the endoplasmic reticulum.<ref name=":1" /> ==Genotypes== {{details|Hepatitis C#Epidemiology}} Based on genetic differences between HCV isolates, the hepatitis C virus species is classified into six [[genotypes]] (1–6) with several subtypes within each genotype (represented by lower-cased letters).<ref name=Simmonds1993>{{cite journal |vauthors=Simmonds P, Holmes EC, Cha TA, etal |title=Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region |journal=J. Gen. Virol. |volume=74 |issue=Pt 11 |pages=2391–9 |date=November 1993 |pmid=8245854 |url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=8245854 |doi = 10.1099/0022-1317-74-11-2391 }}</ref><ref name=Nakano>{{cite journal|last=Nakano|first=Tatsunori|title=An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region|journal=Liver International|date=9 October 2011|doi=10.1111/j.1478-3231.2011.02684.x|pmid=22142261|volume=32|issue=2|pages=339–45|first2=Gillian M. G.|last3=Lau|first3=Grace M. L.|last4=Sugiyama|first4=Masaya|last5=Mizokami|first5=Masashi|last2=Lau}}</ref> Subtypes are further broken down into quasispecies based on their genetic diversity. Genotypes differ by 30–35% of the nucleotide sites over the complete genome.<ref name=Ohno2007>{{cite journal |vauthors=Ohno O, Mizokami M, Wu RR, Saleh MG, Ohba K, Orito E, Mukaide M, Williams R, Lau JY, etal | year = 2007 | title = New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a | journal = J Clin Microbiol | volume = 35 | issue = 1| pages = 201–7 | pmid = 8968908 | pmc = 229539 }}</ref> The difference in genomic composition of subtypes of a genotype is usually 20–25%. Subtypes 1a and 1b are found worldwide and cause 60% of all cases. ===Clinical importance=== {{Outdated as of | topic = direct-acting antiviral medications}} Genotype is clinically important in determining potential response to [[interferon]]-based therapy and the required duration of such therapy. Genotypes 1 and 4 are less responsive to [[interferon]]-based treatment than are the other genotypes (2, 3, 5 and 6).<ref name="simmonds">{{cite journal | author = Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, Halfon P, Inchauspé G, Kuiken C, Maertens G, Mizokami M, Murphy D, Okamoto H, Pawlotsky J, Penin F, Sablon E, Shin-I T, Stuyver L, Thiel H, Viazov S, Weiner A, Widell A | title = Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes | journal = Hepatology | volume = 42 | issue = 4 | pages = 962–73 | year = 2005 | pmid = 16149085 | doi = 10.1002/hep.20819 | last12 = Murphy | first12 = DG | last13 = Okamoto | first13 = H | last14 = Pawlotsky | first14 = JM | last15 = Penin | first15 = F | last16 = Sablon | first16 = E | last17 = Shin-I | first17 = T | last18 = Stuyver | first18 = LJ | last19 = Thiel | first19 = HJ | last20 = Viazov | first20 = S | last21 = Weiner | first21 = AJ | last22 = Widell | first22 = A| last2 = Bukh | last3 = Combet | last4 = Deléage | last5 = Enomoto | last6 = Feinstone | last7 = Halfon | last8 = Inchauspé | last9 = Kuiken | last10 = Maertens | last11 = Mizokami }}</ref> The duration of standard interferon-based therapy for genotypes 1 and 4 is 48 weeks, whereas treatment for genotypes 2 and 3 is completed in 24 weeks. Sustained virological responses occur in 70% of genotype 1 cases, ~90% of genotypes 2 and 3, ~65% of genotype 4 and ~80% of genotype 6.<ref name=Yu2009>{{cite journal | author = Yu ML, Chuang WL | year = 2009 | title = Treatment of chronic hepatitis C in Asia: when East meets West | journal = J Gastroenterol Hepatol | volume = 24 | issue = 3| pages = 336–345 | doi = 10.1111/j.1440-1746.2009.05789.x | pmid = 19335784 | last2 = Chuang }}</ref> In addition people of African descent are much less likely to clear the infection when infected with genotypes 1 or 4 <ref>{{cite journal|last1=Muir|first1=AJ|last2=Bornstein|first2=JD|last3=Killenberg|first3=PG|last4=Atlantic Coast Hepatitis Treatment Group|title=Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites.|journal=N Engl J Med|date=2004 |volume=350|issue=|pages=2265–71|pmid=15163776|doi=10.1056/NEJMoa032502 }} Erratum: {{DOI|10.1056/nejm200409163511229}}</ref> and substantial proportion of this lack of response to treatment has been traced down to a single nucleotide polymorphism (SNP) on chromosome 19 that is predictive of treatment success.<ref>{{cite journal|last1=Ge|first1=D|last2=Fellay|first2=J|last3=Thompson|first3=AJ|last4=Simon|first4=SJ|last5=Shianna|first5=KV|last6=Urban|first6=TJ|last7=Heinzen|first7=EL|last8=et|first8=al.|title=Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance|journal=Nature|date=2009|volume=461|issue=7262|pages=399–401|pmid=19684573|doi=10.1038/nature08309|bibcode=2009Natur.461..399G}}</ref> HCV genotypes 1 and 4 have been distributed endemically in overlapping areas of West and Central Africa, infecting for centuries human populations carrying the genetic polymorphism in question. This has prompted scientists to suggest that the protracted persistence of HCV genotypes 1 and 4 in people of African origin is an evolutionary adaptation over many centuries to these populations’ immunogenetic responses.<ref>{{cite journal|last1=Rose|first1=R|last2=Markov|first2=PV|last3=Lam|first3=TT|last4=Pybus|first4=OG|title=Viral evolution explains the associations among hepatitis C virus genotype, clinical outcomes, and human genetic variation|journal=Infect Genet Evol|date=2013|volume=20|pages=418–21|pmid=24140473|doi=10.1016/j.meegid.2013.09.029}}</ref> Infection with one genotype does not confer immunity against others, and concurrent infection with two strains is possible. In most of these cases, one of the strains removes the other from the host in a short time. This finding opens the door to replacing strains non-responsive to medication with others easier to treat.<ref>{{cite journal | author = Laskus T, Wang LF, Radkowski M, Vargas H, Nowicki M, Wilkinson J, Rakela J. | title = Exposure of hepatitis C virus (HCV) RNA-positive recipients to HCV RNA-positive blood donors results in rapid predominance of a single donor strain and exclusion and/or suppression of the recipient strain | journal = Journal of Virology| volume = 75| issue = 5| pages = 2059–66| year = 2001| pmid = 11160710 | doi =10.1128/JVI.75.5.2059-2066.2001 | pmc = 114790 | last2 = Wang | last3 = Radkowski | last4 = Vargas | last5 = Nowicki | last6 = Wilkinson | last7 = Rakela }}</ref> ==Epidemiology== Hepatitis C virus is predominantly a blood-borne virus, with very low risk of sexual or vertical transmission.<ref name = "Shepard2005">{{cite journal|last1=Shepard|first1=CW|last2=Finelli|first2=L|last3=Alter|first3=MJ|title=Global epidemiology of hepatitis C virus infection.|journal=Lancet Infect Dis|date=Sep 2005|volume=5|issue=9|pages=558–67|pmid=16122679|url=http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2805%2970216-4/fulltext |doi=10.1016/S1473-3099(05)70216-4}}</ref> Because of this mode of spread the key groups at risk are injecting drug users (IDUs), recipients of blood products and sometimes patients on haemodialysis. Common setting for transmission of HCV is also intra-hospital (nosocomial) transmission, when practices of hygiene and sterilization are not correctly followed in the clinic.<ref>{{cite journal|last1=Alter|first1=MJ|title=HCV routes of transmission: what goes around comes around|journal=Semin Liver Dis|date=Nov 2011|volume=31|issue=4|pages=340–6|pmid=22189974|doi=10.1055/s-0031-1297923}}</ref> A number of cultural or ritual practices have been proposed as a potential historical mode of spread for hepatitis C virus, including circumcision, genital mutilation, ritual scarification, traditional tattooing and acupuncture.<ref name="Shepard2005" /> It has also been argued that given the extremely prolonged periods of persistence of HCV in humans, even very low and undetectable rates of mechanical transmission via biting insects may be sufficient to maintain endemic infection in the tropic, where people receive large number of insect bites.<ref>{{cite journal|last1=Pybus|first1=OG|last2=Markov|first2=PV|last3=Wu|first3=A|last4=Tatem|first4=AJ|title=Investigating the endemic transmission of the hepatitis C virus|journal=Int J Parasitol|date=Jul 2007|volume=37|issue=8–9|pages=839–49|pmid=17521655|doi=10.1016/j.ijpara.2007.04.009}}</ref> ==Evolution== Identification of the origin of this virus has been difficult but genotypes 1 and 4 appear to share a common origin.<ref name=Salemi2002>{{cite journal | author = Salemi M, Vandamme AM | year = 2002 | title = Hepatitis C virus evolutionary patterns studied through analysis of full-genome sequences | journal = J Mol Evol | volume = 54 | issue = 1| pages = 62–70 | doi = 10.1007/s00239-001-0018-9 | pmid = 11734899 | last2 = Vandamme | bibcode = 2002JMolE..54...62S }}</ref> A [[Bayesian probability|Bayes]]ian analysis suggests that the major genotypes diverged about 300–400 years ago from the ancestor virus.<ref name=Sarwar2011>{{cite journal |author=Sarwar MT, Kausar H, Ijaz B |title=NS4A protein as a marker of HCV history suggests that different HCV genotypes originally evolved from genotype 1b |journal=Virol. J. |volume=8 |pages=317 |year=2011 |pmid=21696641 |pmc=3145594 |doi=10.1186/1743-422X-8-317 |url=http://www.virologyj.com/content/8J Viral Hepat. 1997;4 Suppl 1:69–74. Investigation of the pattern of diversity of hepatitis C virus in relation to times of transmission. Simmonds P, Smith DB.//317|author2=and others |displayauthors=1 |last3=Ijaz |last4=Ahmad |last5=Ansar |last6=Sumrin |last7=Ashfaq |last8=Asad |last9=Gull |last10=Shahid |last11=Hassan }}</ref> The minor genotypes diverged about 200 years ago from their major genotypes. All of the extant genotypes appear to have evolved from genotype 1 subtype 1b. A study of genotype 6 strains suggests an earlier date of evolution: ∼1,100 to 1,350 years before the present (95% credible region, 600 to >2,500 years ago).<ref name=Pybus2009>{{cite journal |vauthors=Pybus OG, Barnes E, Taggart R, Lemey P, Markov PV, Rasachak B, Syhavong B, Phetsouvanah R, Sheridan I, etal | year = 2009 | title = Genetic history of hepatitis C virus in East Asia | journal = J Virol | volume = 83 | issue = 2| pages = 1071–82 | doi = 10.1128/JVI.01501-08 | pmid = 18971279 | pmc = 2612398 }}</ref> The estimated rate of mutation was 1.8 × 10⁻⁴ (95% credible region 0.9 × 10⁻⁴ to 2.9 × 10⁻⁴). This genotype may be the ancestor of the other genotypes.<ref name="Pybus2009"/> A study of European, USA and Japanese isolates suggested that the date of origin of genotype 1b was ~1925.<ref name=Simmonds1997>{{cite journal | author = Simmonds P, Smith DB | year = 1997 | title = Investigation of the pattern of diversity of hepatitis C virus in relation to times of transmission | journal = J Viral Hepat | volume = 4 | issue = Suppl 1| pages = 69–74 | doi = 10.1111/j.1365-2893.1997.tb00163.x | pmid = 9097281 | last2 = Smith }}</ref> The estimated dates of origin of types 2a and 3a were 1917 and 1943 respectively. The time of divergence of types 1a and 1b was estimated to be 200–300 years. A study of genotype 1a and 1b estimated the dates of origin to be 1914–1930 (95% credible interval: 1802–1957) for type 1a and 1911–1944 (95% credible interval: 1806–1965) for type 1b.<ref name=Magiorkinis2009>{{cite journal |vauthors=Magiorkinis G, Magiorkinis E, Paraskevis D, etal |title=The global spread of hepatitis C virus 1a and 1b: a phylodynamic and phylogeographic analysis |journal=PLoS Med. |volume=6 |issue=12 |pages=e1000198 |date=December 2009 |pmid=20041120 |pmc=2795363 |doi=10.1371/journal.pmed.1000198 |url=http://dx.plos.org/10.1371/journal.pmed.1000198 }}</ref> Both types 1a and 1b underwent massive expansions in their effective population size between 1940 and 1960. The expansion of HCV subtype 1b preceded that of subtype 1a by at least 16 years (95% credible interval: 15–17 years). Both types appear to have spread from the developed world to the developing world. The genotype 2 strains from Africa can be divided into four clades that correlate with their country of origin: (1) Cameroon and Central African Republic (2) Benin, Ghana and Burkina Faso (3) Gambia, Guinea, Guinea-Bissau and Senegal (4) Madagascar.<ref name=Markov2009>{{cite journal |author=Markov PV, Pepin J, Frost E, Deslandes S, Labbé AC, Pybus OG |title=Phylogeography and molecular epidemiology of hepatitis C virus genotype 2 in Africa |journal=J. Gen. Virol. |volume=90 |issue=Pt 9 |pages=2086–96 |date=September 2009 |pmid=19474244 |doi=10.1099/vir.0.011569-0 |url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=19474244|last2=Pepin |last3=Frost |last4=Deslandes |last5=Labbé |last6=Pybus }}</ref> There is also strong evidence now for the dissemination of hepatitis C virus genotype 2 from West Africa to the Caribbean by the Trans-Atlantic slave trade <ref>{{cite journal|last1=Markov|first1=PV|last2=van de Laar|first2=TJ|last3=Thomas|first3=XV|last4=Aronson|first4=SJ|last5=Weegink|first5=CJ|last6=van den Berk|first6=GE|last7=Prins|first7=M.|title=Colonial History and Contemporary Transmission Shape the Genetic Diversity of Hepatitis C Virus Genotype 2 in Amsterdam|journal=J Virol|date=2012|volume=86|issue=14|pages=7677–7687|doi=10.1128/JVI.06910-11|pmid=22573865|display-authors=etal|pmc=3416291}}</ref> Genotype 3 is thought to have its origin in South East Asia.<ref name=Simmonds2004>{{cite journal |author=Simmonds P |title=Genetic diversity and evolution of hepatitis C virus—15 years on |journal=J. Gen. Virol. |volume=85 |issue=Pt 11 |pages=3173–88 |date=November 2004 |pmid=15483230 |doi=10.1099/vir.0.80401-0 |url=http://vir.sgmjournals.org/cgi/pmidlookup?view=long&pmid=15483230}}</ref> These dates from these various countries suggests that this virus may have evolved in South East Asia and was spread to West Africa by traders from Western Europe.<ref name=Simmonds2001>{{cite journal | author = Simmonds P | year = 2001 | title = Reconstructing the origins of human hepatitis viruses | journal = Philos Trans R Soc Lond B Biol Sci | volume = 356 | issue = 1411| pages = 1013–26 | doi = 10.1098/rstb.2001.0890 | pmid = 11516379 | pmc = 1088496 }}</ref> It was later introduced into Japan once that [[Sakoku|country's self-imposed isolation]] was lifted. Once introduced to a country its spread has been influenced by many local factors including blood transfusions, vaccination programmes, intravenous drug use and treatment regimes. Given the reduction in the rate of spread once screening for Hepatitis C in blood products was implemented in the 1990s it would seem that at least in recent times blood transfusion has been an important method of spreading for this virus. Additional work is required to determine the dates of evolution of the various genotypes and the timing of their spread across the globe. ==Vaccination== {{Main|Hepatitis C vaccine}} Unlike hepatitis A and B, there is currently no [[vaccine]] to prevent hepatitis C infection.<ref>{{cite journal|pmid=20625493 | doi=10.1155/2010/548280 | volume=2010 | title=A new insight into hepatitis C vaccine development | pmc=2896694 | year=2010 | author=Yu CI, Chiang BL | journal=J. Biomed. Biotechnol. | pages=548280| last2=Chiang }}</ref> ==Current research== The study of HCV has been hampered by the narrow host range of HCV.<ref>{{Cite journal | last1 = Rauch | first1 = A. | last2 = Gaudieri | first2 = S. | last3 = Thio | first3 = C. | last4 = Bochud | first4 = P. Y. | title = Host genetic determinants of spontaneous hepatitis C clearance | journal = Pharmacogenomics | volume = 10 | issue = 11 | pages = 1819–1837 | year = 2009 | pmid = 19891557 | doi = 10.2217/pgs.09.121}}</ref> The use of [[Replicon (genetics)|replicons]] has been successful but these have only been recently discovered.<ref name="pmid19344246">{{cite journal | author = Meier V, Ramadori G | title = Hepatitis C virus virology and new treatment targets | journal = Expert Rev Anti Infect Ther | volume = 7 | issue = 3 | pages = 329–50 |date=April 2009 | pmid = 19344246 | doi = 10.1586/eri.09.12 | url = http://www.future-drugs.com/doi/abs/10.1586/eri.09.12?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov| accessdate = 2009-04-16| last2 = Ramadori }}</ref> HCV, as with most [[RNA]] viruses, exists as a [[viral quasispecies]], making it very difficult to isolate a single strain or receptor type for study.<ref>{{cite journal |author=Manns MP, Foster GR, Rockstroh JK, Zeuzem S, Zoulim F, Houghton M |title=The way forward in HCV treatment—finding the right path |journal=Nat Rev Drug Discov |volume=6 |issue=12 |pages=991–1000 |date=December 2007 |pmid=18049473 |doi=10.1038/nrd2411 |last2=Foster |last3=Rockstroh |last4=Zeuzem |last5=Zoulim |last6=Houghton }}</ref><ref>{{cite journal |last1=Ahmed |first1=Ali Mahmoud |last2=Doheim |first2=Mohamed Fahmy |last3=Mattar |first3=Omar Mohamed |last4=Sherif |first4=Nourin Ali |last5=Truong |first5=Duy Hieu |last6=Pham T.L. |first6=Hoa |last7=Hirayama |first7=Kenji |last8=Huy |first8=Nguyen Tien |title=Beclabuvir in combination with asunaprevir and daclatasvir for hepatitis C virus genotype 1 infection: A systematic review and meta-analysis |journal=J Med Virol |date=May 2018 |volume=90 |issue=5 |pages=907-918. |doi=10.1002/jmv.24947 |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.24947}}</ref> [[File:HCV IRES.svg|right|thumb|Structure of the IRES located in the 5'-UTR of HCV]] Current research is focused on small-molecule inhibitors of the viral [[Protease inhibitor (pharmacology)|protease]], [[RNA polymerase]] and other nonstructural genes. Two agents — [[Boceprevir]] by Merck<ref>{{cite web |publisher=FDA | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm255390.htm |title=FDA approves Victrelis for Hepatitis C |format=press release |date=May 13, 2011}}</ref> and [[Incivek|Telaprevir]] by Vertex Pharmaceuticals Inc—both inhibitors of NS3 protease were approved for use on May 13, 2011 and May 23, 2011 respectively. A possible association between low [[Vitamin D]] levels and a poor response to treatment has been reported.<ref name=Gutierrez2011>{{cite journal | author = Gutierrez JA, Parikh N, Branch AD | year = 2011 | title = Classical and emerging roles of vitamin d in hepatitis C virus infection | journal = Semin Liver Dis | volume = 31 | issue = 4| pages = 387–398 | doi = 10.1055/s-0031-1297927 | pmid = 22189978 | pmc = 4107414 | last2 = Parikh | last3 = Branch }}</ref><ref name=Lange2011>{{cite journal |vauthors=Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J, Herrmann E, Badenhoop K, Zeuzem S, etal | year = 2011 | title = Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy | journal = J Hepatol | volume = 54 | issue = 5| pages = 887–893 | doi = 10.1016/j.jhep.2010.08.036 | pmid = 21145801 }}</ref><ref name=Baur2011>{{cite journal |vauthors=Baur K, Mertens JC, Schmitt J, etal |title=The vitamin D receptor gene bAt (CCA) haplotype impairs the response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C patients |journal=Antivir. Ther. (Lond.) |volume=17 |issue=3 |pages=541–7 |year=2012 |pmid=22300961 |doi=10.3851/IMP2018 }}</ref><ref>{{cite journal |vauthors=Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E, Pasino M, Ieluzzi D, Cussigh A, etal | year = 2011 | title = Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C | journal = Hepatology | volume = 53 | issue = 4| pages = 1118–26 | doi = 10.1002/hep.24201 | pmid = 21480318 }}</ref> ''In vitro'' work has shown that Vitamin D may be able to reduce viral replication.<ref name=Gal-Tanamy2011>{{cite journal | author = Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa R, Zemel R | year = 2011 | title = Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes | journal = Hepatology | volume = 54 | issue = 5| pages = 1570–9 | doi = 10.1002/hep.24575 | pmid = 21793032 | last2 = Bachmetov | last3 = Ravid | last4 = Koren | last5 = Erman | last6 = Tur-Kaspa | last7 = Zemel }}</ref> While this work looks promising<ref name=Abu-Mouch2011>{{cite journal | author = Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N | year = 2011 | title = Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients | journal = World J Gastroenterol | volume = 17 | issue = 47| pages = 5184–90 | doi = 10.3748/wjg.v17.i47.5184 | pmid = 22215943 | pmc = 3243885 | last2 = Fireman | last3 = Jarchovsky | last4 = Zeina | last5 = Assy }}</ref><ref>{{cite journal |vauthors=Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, Bignulin S, Cmet S, Fontanini E, etal | year = 2011 | title = Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C | journal = Transpl Int | volume = 24 | issue = 1| pages = 43–50 | doi = 10.1111/j.1432-2277.2010.01141.x | pmid = 20649944 }}</ref> the results of clinical trials are awaited.<ref name=Cholongitas2012>{{cite journal |author=Cholongitas E, Theocharidou E, Goulis J, Tsochatzis E, Akriviadis E, Burroughs K |title=Review article: the extra-skeletal effects of vitamin D in chronic hepatitis C infection |journal=Aliment. Pharmacol. Ther. |volume=35 |issue=6 |pages=634–46 |date=March 2012 |pmid=22316435 |doi=10.1111/j.1365-2036.2012.05000.x |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0269-2813&date=2012&volume=35&issue=6&spage=634|last2=Theocharidou |last3=Goulis |last4=Tsochatzis |last5=Akriviadis |last6=Burroughs }}</ref><ref name=Cacopardo2012>{{cite journal |vauthors=Cacopardo B, Camma C, Petta S, Pinzone MR, Cappellani A, Zanghi A, Nicolosi A, Nunnari G | year = 2012 | title = Diagnostic and therapeutical role of vitamin D in chronic hepatitis C virus infection | journal = Front Biosci | volume = 1 | issue = 4| pages = 1276–1286 }}</ref> However, it has been proposed that Vitamin D supplementation is important in addition to standard treatment, in order to enhance treatment response.<ref name=":0">{{Cite journal|title = Alternative medications in Hepatitis C infection|last = Halegoua-De Marzio|first = Dina|date = January 27, 2014|journal = World Journal of Hepatology|doi = 10.4254/wjh.v6.i1.9|pmid = 24653790|last2 = Fenkel|first2 = Jonathan| volume=6 |issue=1 |pages=9–16 |pmc=3953807}}</ref> Naringenin has been shown to block the assembly of intracellular infectious viral particles without affecting intracellular levels of the viral RNA or protein. Although the research is relatively new, naringenin may offer new insight into HCV therapeutic target.<ref name=":0" /> Other agents that are under investigation include [[nucleoside analogues|nucleoside and nucleotide analogue]] inhibitors and non nucleoside inhibitors of the RNA dependent RNA polymerase, inhibitors of nonstructural protein 5A and host targeted compounds such as [[cyclophilin]] inhibitors and [[silibinin]].<ref name=Sarrazin2012>{{cite journal |author=Sarrazin C, Hézode C, Zeuzem S, Pawlotsky JM |title=Antiviral strategies in hepatitis C virus infection |journal=J. Hepatol. |volume=56 |issue=Suppl 1|pages=S88–100 |year=2012 |pmid=22300469 |doi=10.1016/S0168-8278(12)60010-5 |url=http://linkinghub.elsevier.com/retrieve/pii/S0168-8278(12)60010-5|last2=Hézode |last3=Zeuzem |last4=Pawlotsky }}</ref> [[Sofosbuvir]] for use against chronic hepatitis C infection was approved by the FDA December 6, 2013. It has been reported to be the first drug that has demonstrated safety and efficacy to treat certain types of HCV infection without the need for co-administration of interferon.<ref>[http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm377888.htm Press announcement, FDA, December 6 2013]</ref> On November 22, the FDA approved [[simeprevir]] for use in combination with [[peginterferon-alfa]] and [[ribavirin]].<ref>{{cite web | url = http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376449.htm | title = FDA approves new treatment for hepatitis C virus | publisher = [[Food and Drug Administration]] | date = Nov 22, 2013}}</ref> Simeprevir has been approved in Japan for the treatment of chronic hepatitis C infection, genotype 1.<ref>{{cite web | url = https://www.wsj.com/article/PR-CO-20130927-900120.html | title = Medivir: Simeprevir has been approved in Japan for the treatment of genotype 1 chronic hepatitis C infection | date = September 27, 2013 | publisher = The Wall Street Journal}}</ref> There is also current experimental research on non drug related therapies. Oxymatrine, for example, is a root extract found in the continent of Asia that has been reported to have antiviral activity against HCV in cell cultures and animal studies. Small and promising human trials have shown no serious side effects and beneficial results, but they were too small to generalize conclusions.<ref name=":0" /> ==See also== * [[Oncovirus|Cancer virus]] * [[Hepatitis C virus internal ribosome entry site|HCV IRES]] * [[Hepatitis C virus stem-loop VII]] * [[Hepatitis C virus 3'X element]] * [[Hepatitis C virus (HCV) cis-acting replication element (CRE)]] *[[Discovery and development of NS5A inhibitors]] ==References== {{Reflist|30em}} == External links == * [http://www.hivandhepatitis.com/hep_c/hepc_news_genotype.html Academic articles about the HCV six genotypes] [[Clodovero Ferri]] * [http://hcv.lanl.gov/ HCV Sequence and Immunology Databases] at Los Alamos National Laboratory * [http://www.viprbrc.org/brc/home.do?decorator=flavi Virus Pathogen Database and Analysis Resource (ViPR): Flaviviridae] {{Viral diseases}} {{Taxonbar|from=Q708693}} {{DEFAULTSORT:Hepatitis C Virus}} [[Category:Hepatitis C virus]]'