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dc.contributor.authorAlhammad, YMO
dc.contributor.authorMaharajh, S
dc.contributor.authorButcher, R
dc.contributor.authorEden, J-S
dc.contributor.authorWhite, PA
dc.contributor.authorPoumbourios, P
dc.contributor.authorDrummer, HE
dc.date.accessioned2020-12-21T03:43:45Z
dc.date.available2020-12-21T03:43:45Z
dc.date.issued2015-05-13
dc.identifierpii: PONE-D-15-03196
dc.identifier.citationAlhammad, Y. M. O., Maharajh, S., Butcher, R., Eden, J. -S., White, P. A., Poumbourios, P. & Drummer, H. E. (2015). Longitudinal Sequence and Functional Evolution within Glycoprotein E2 in Hepatitis C Virus Genotype 3a Infection. PLOS ONE, 10 (5), https://doi.org/10.1371/journal.pone.0126397.
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/11343/257328
dc.description.abstractThe E2 glycoprotein of Hepatitis C virus (HCV) is a major target of the neutralizing antibody (NAb) response with the majority of epitopes located within its receptor binding domain (RBD; 384-661). Within E2 are three variable regions located at the N-terminus (HVR1; 384-411), and internally at 460-480 (HVR2) and 570-580 [intergenotypic variable region (igVR)], all of which lie outside a conserved core domain that contains the CD81 binding site, essential for attachment of virions to host cells and a major target of NAbs. In this study, we examined the evolution of the E1 and E2 region in two patients infected with genotype 3a virus. Whereas one patient was able to clear the acute infection, the other developed a chronic infection. Mutations accumulated at multiple positions within the N-terminal HVR1 as well as within the igVR in both patients over time, whereas mutations in HVR2 were observed only in the chronically infected patient. Mutations within or adjacent to the CD81 contact site were observed in both patients but were less frequent and more conservative in the patient that cleared his/her infection. The evolution of CD81 binding function and antigenicity was examined with longitudinal E2 RBD sequences. The ability of the RBD to bind CD81 was completely lost by week 108 in the patient that developed chronic HCV. In the second patient, the ability of the week 36 RBD, just prior to viral clearance, to bind CD81 was reduced ~50% relative to RBD sequences obtained earlier. The binding of a NAb specific to a conserved epitope located within E2 residues 411-428 was significantly reduced by week 108 despite complete conservation of its epitope suggesting that E2 antigenicity is allosterically modulated. The exposure of non-neutralizing antibody epitopes was similarly explored and we observed that the epitope of 3 out of 4 non-NAbs were significantly more exposed in the RBDs representing the late timepoints in the chronic patient. By contrast, the exposure of non-neutralizing epitopes was reduced in the patient that cleared his/her infection and could in part be attributed to sequence changes in the igVR. These studies reveal that during HCV infection, the exposure of the CD81 binding site on E2 becomes increasingly occluded, and the antigenicity of the E2 RBD towards both neutralizing and non-neutralizing antibodies is modulated via allosteric mechanisms.
dc.languageEnglish
dc.publisherPUBLIC LIBRARY SCIENCE
dc.titleLongitudinal Sequence and Functional Evolution within Glycoprotein E2 in Hepatitis C Virus Genotype 3a Infection
dc.typeJournal Article
dc.identifier.doi10.1371/journal.pone.0126397
melbourne.affiliation.departmentMicrobiology and Immunology
melbourne.source.titlePLoS One
melbourne.source.volume10
melbourne.source.issue5
dc.rights.licenseCC BY
melbourne.elementsid1264777
melbourne.contributor.authorDrummer, Heidi
dc.identifier.eissn1932-6203
melbourne.accessrightsOpen Access


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