The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.
Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation...
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2013
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oai:doaj.org-article:2904622cd3c446a68927030a0ec4fe052021-11-18T06:07:19ZThe effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.1553-73661553-737410.1371/journal.ppat.1003754https://doaj.org/article/2904622cd3c446a68927030a0ec4fe052013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24278016/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121-134 but were still capable of neutralizing roughly 40-80% of PGT121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121-134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121-134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.Devin SokUri LasersonJonathan LasersonYi LiuFrancois VigneaultJean-Philippe JulienBryan BrineyAlejandra RamosKaren F SayeKhoa LeAlison MahanShenshen WangMehran KardarGur YaariLaura M WalkerBirgitte B SimenElizabeth P St JohnPo-Ying Chan-HuiKristine SwiderekSteven H KleinsteinGalit AlterMichael S SeamanArup K ChakrabortyDaphne KollerIan A WilsonGeorge M ChurchDennis R BurtonPascal PoignardPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 11, p e1003754 (2013) |
| institution |
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| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Devin Sok Uri Laserson Jonathan Laserson Yi Liu Francois Vigneault Jean-Philippe Julien Bryan Briney Alejandra Ramos Karen F Saye Khoa Le Alison Mahan Shenshen Wang Mehran Kardar Gur Yaari Laura M Walker Birgitte B Simen Elizabeth P St John Po-Ying Chan-Hui Kristine Swiderek Steven H Kleinstein Galit Alter Michael S Seaman Arup K Chakraborty Daphne Koller Ian A Wilson George M Church Dennis R Burton Pascal Poignard The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. |
| description |
Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121-134 but were still capable of neutralizing roughly 40-80% of PGT121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121-134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121-134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design. |
| format |
article |
| author |
Devin Sok Uri Laserson Jonathan Laserson Yi Liu Francois Vigneault Jean-Philippe Julien Bryan Briney Alejandra Ramos Karen F Saye Khoa Le Alison Mahan Shenshen Wang Mehran Kardar Gur Yaari Laura M Walker Birgitte B Simen Elizabeth P St John Po-Ying Chan-Hui Kristine Swiderek Steven H Kleinstein Galit Alter Michael S Seaman Arup K Chakraborty Daphne Koller Ian A Wilson George M Church Dennis R Burton Pascal Poignard |
| author_facet |
Devin Sok Uri Laserson Jonathan Laserson Yi Liu Francois Vigneault Jean-Philippe Julien Bryan Briney Alejandra Ramos Karen F Saye Khoa Le Alison Mahan Shenshen Wang Mehran Kardar Gur Yaari Laura M Walker Birgitte B Simen Elizabeth P St John Po-Ying Chan-Hui Kristine Swiderek Steven H Kleinstein Galit Alter Michael S Seaman Arup K Chakraborty Daphne Koller Ian A Wilson George M Church Dennis R Burton Pascal Poignard |
| author_sort |
Devin Sok |
| title |
The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. |
| title_short |
The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. |
| title_full |
The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. |
| title_fullStr |
The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. |
| title_full_unstemmed |
The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies. |
| title_sort |
effects of somatic hypermutation on neutralization and binding in the pgt121 family of broadly neutralizing hiv antibodies. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/2904622cd3c446a68927030a0ec4fe05 |
| work_keys_str_mv |
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