Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape

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dc.contributor.authorWibmer, Constantinos Kurt
dc.contributor.authorGorman, Jason
dc.contributor.authorOzorowski, Gabriel
dc.contributor.authorBhiman, Jinal N
dc.contributor.authorSheward, Daniel J
dc.contributor.authorJoyce, M Gordon
dc.contributor.authorAsokan, Mangai
dc.contributor.authorBurton, Dennis R
dc.contributor.authorConnors, Mark
dc.contributor.authorAbdool Karim, Salim S
dc.contributor.authorMascola, John R
dc.contributor.authorRobinson, James E
dc.contributor.authorWard, Andrew B
dc.contributor.authorKwong, Peter D
dc.contributor.authorMorris, Lynn
dc.contributor.authorMoore, Penny L
dc.date.accessioned2021-10-08T07:15:54Z
dc.date.available2021-10-08T07:15:54Z
dc.date.issued2017
dc.description.abstractA comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagenesis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epitopes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N- or O-linked glycosylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing antibodies and identifies a set of mutations in the gp120 C terminus that exposes the membrane-proximal external region of gp41, with potential utility in HIV vaccine design.
dc.identifier.apacitationWibmer, C. K., Gorman, J., Ozorowski, G., Bhiman, J. N., Sheward, D. J., Joyce, M. G., ... Moore, P. L. (2017). Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape. <i>PLoS Pathogens</i>, 13(1), e1006074 - 177. http://hdl.handle.net/11427/34718en_ZA
dc.identifier.chicagocitationWibmer, Constantinos Kurt, Jason Gorman, Gabriel Ozorowski, Jinal N Bhiman, Daniel J Sheward, M Gordon Joyce, Mangai Asokan, et al "Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape." <i>PLoS Pathogens</i> 13, 1. (2017): e1006074 - 177. http://hdl.handle.net/11427/34718en_ZA
dc.identifier.citationWibmer, C.K., Gorman, J., Ozorowski, G., Bhiman, J.N., Sheward, D.J., Joyce, M.G., Asokan, M. & Burton, D.R. et al. 2017. Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape. <i>PLoS Pathogens.</i> 13(1):e1006074 - 177. http://hdl.handle.net/11427/34718en_ZA
dc.identifier.issn1553-7366
dc.identifier.issn1553-7374
dc.identifier.ris TY - Journal Article AU - Wibmer, Constantinos Kurt AU - Gorman, Jason AU - Ozorowski, Gabriel AU - Bhiman, Jinal N AU - Sheward, Daniel J AU - Joyce, M Gordon AU - Asokan, Mangai AU - Burton, Dennis R AU - Connors, Mark AU - Abdool Karim, Salim S AU - Mascola, John R AU - Robinson, James E AU - Ward, Andrew B AU - Kwong, Peter D AU - Morris, Lynn AU - Moore, Penny L AB - A comprehensive understanding of the regions on HIV-1 envelope trimers targeted by broadly neutralizing antibodies may contribute to rational design of an HIV-1 vaccine. We previously identified a participant in the CAPRISA cohort, CAP248, who developed trimer-specific antibodies capable of neutralizing 60% of heterologous viruses at three years post-infection. Here, we report the isolation by B cell culture of monoclonal antibody CAP248-2B, which targets a novel membrane proximal epitope including elements of gp120 and gp41. Despite low maximum inhibition plateaus, often below 50% inhibitory concentrations, the breadth of CAP248-2B significantly correlated with donor plasma. Site-directed mutagenesis, X-ray crystallography, and negative-stain electron microscopy 3D reconstructions revealed how CAP248-2B recognizes a cleavage-dependent epitope that includes the gp120 C terminus. While this epitope is distinct, it overlapped in parts of gp41 with the epitopes of broadly neutralizing antibodies PGT151, VRC34, 35O22, 3BC315, and 10E8. CAP248-2B has a conformationally variable paratope with an unusually long 19 amino acid light chain third complementarity determining region. Two phenylalanines at the loop apex were predicted by docking and mutagenesis data to interact with the viral membrane. Neutralization by CAP248-2B is not dependent on any single glycan proximal to its epitope, and low neutralization plateaus could not be completely explained by N- or O-linked glycosylation pathway inhibitors, furin co-transfection, or pre-incubation with soluble CD4. Viral escape from CAP248-2B involved a cluster of rare mutations in the gp120-gp41 cleavage sites. Simultaneous introduction of these mutations into heterologous viruses abrogated neutralization by CAP248-2B, but enhanced neutralization sensitivity to 35O22, 4E10, and 10E8 by 10-100-fold. Altogether, this study expands the region of the HIV-1 gp120-gp41 quaternary interface that is a target for broadly neutralizing antibodies and identifies a set of mutations in the gp120 C terminus that exposes the membrane-proximal external region of gp41, with potential utility in HIV vaccine design. DA - 2017 DB - OpenUCT DP - University of Cape Town IS - 1 J1 - PLoS Pathogens LK - https://open.uct.ac.za PY - 2017 SM - 1553-7366 SM - 1553-7374 T1 - Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape TI - Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape UR - http://hdl.handle.net/11427/34718 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/34718
dc.identifier.vancouvercitationWibmer CK, Gorman J, Ozorowski G, Bhiman JN, Sheward DJ, Joyce MG, et al. Structure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape. PLoS Pathogens. 2017;13(1):e1006074 - 177. http://hdl.handle.net/11427/34718.en_ZA
dc.publisher.departmentInstitute of Infectious Disease and Molecular Medicine
dc.publisher.facultyFaculty of Health Sciences
dc.sourcePLoS Pathogens
dc.source.journalissue1
dc.source.journalvolume13
dc.source.paginatione1006074 - 177
dc.source.urihttps://dx.doi.org/10.1371/journal.ppat.1006074
dc.subject.otherBiology and Life Sciences
dc.subject.otherPhysiology
dc.subject.otherImmune Physiology
dc.subject.otherAntibodies
dc.subject.otherMedicine and Health Sciences
dc.subject.otherImmunology
dc.subject.otherImmune System Proteins
dc.subject.otherBiochemistry
dc.subject.otherProteins
dc.subject.otherMicrobiology
dc.subject.otherMedical Microbiology
dc.subject.otherMicrobial Pathogens
dc.subject.otherViral Pathogens
dc.subject.otherImmunodeficiency Viruses
dc.subject.otherHIV
dc.subject.otherHIV-1
dc.subject.otherPathology and Laboratory Medicine
dc.subject.otherPathogens
dc.subject.otherOrganisms
dc.subject.otherViruses
dc.subject.otherBiology and life sciences
dc.subject.otherRNA viruses
dc.subject.otherRetroviruses
dc.subject.otherLentivirus
dc.subject.otherPhysical Sciences
dc.subject.otherPhysics
dc.titleStructure and Recognition of a Novel HIV-1 gp120-gp41 Interface Antibody that Caused MPER Exposure through Viral Escape
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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