Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes

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dc.contributor.authorWibmer, Constantinos Kurten_ZA
dc.contributor.authorBhiman, Jinal Nen_ZA
dc.contributor.authorGray, Elin Sen_ZA
dc.contributor.authorTumba, Nancyen_ZA
dc.contributor.authorKarim, Salim S Abdoolen_ZA
dc.contributor.authorWilliamson, Carolynen_ZA
dc.contributor.authorMorris, Lynnen_ZA
dc.contributor.authorMoore, Penny Len_ZA
dc.date.accessioned2016-01-11T06:48:41Z
dc.date.available2016-01-11T06:48:41Z
dc.date.issued2013en_ZA
dc.description.abstractIdentifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.en_ZA
dc.identifier.apacitationWibmer, C. K., Bhiman, J. N., Gray, E. S., Tumba, N., Karim, S. S. A., Williamson, C., ... Moore, P. L. (2013). Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes. <i>PLoS One</i>, http://hdl.handle.net/11427/16228en_ZA
dc.identifier.chicagocitationWibmer, Constantinos Kurt, Jinal N Bhiman, Elin S Gray, Nancy Tumba, Salim S Abdool Karim, Carolyn Williamson, Lynn Morris, and Penny L Moore "Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes." <i>PLoS One</i> (2013) http://hdl.handle.net/11427/16228en_ZA
dc.identifier.citationWibmer, C. K., Bhiman, J. N., Gray, E. S., Tumba, N., Abdool, K. S., Williamson, C., ... & Moore, P. L. (2013). Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes. PLoS pathogens, 9(10), e1003738. doi:10.1371/journal.ppat.1003738en_ZA
dc.identifier.ris TY - Journal Article AU - Wibmer, Constantinos Kurt AU - Bhiman, Jinal N AU - Gray, Elin S AU - Tumba, Nancy AU - Karim, Salim S Abdool AU - Williamson, Carolyn AU - Morris, Lynn AU - Moore, Penny L AB - Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies. DA - 2013 DB - OpenUCT DO - 10.1371/journal.ppat.1003738 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2013 T1 - Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes TI - Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes UR - http://hdl.handle.net/11427/16228 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16228
dc.identifier.urihttp://dx.doi.org/10.1371/journal.ppat.1003738
dc.identifier.vancouvercitationWibmer CK, Bhiman JN, Gray ES, Tumba N, Karim SSA, Williamson C, et al. Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes. PLoS One. 2013; http://hdl.handle.net/11427/16228.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDivision of Virologyen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2013 Wibmer et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plospathogensen_ZA
dc.subject.otherAntibodiesen_ZA
dc.subject.otherHIV-1en_ZA
dc.subject.otherChemical neutralizationen_ZA
dc.subject.otherMicrobial mutationen_ZA
dc.subject.otherEnzyme-linked immunoassaysen_ZA
dc.subject.otherAntibody responseen_ZA
dc.subject.otherDeletion mutationen_ZA
dc.subject.otherMonoclonal antibodiesen_ZA
dc.titleViral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypesen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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