Longitudinal Analysis Reveals Early Development of Three MPER-Directed Neutralizing Antibody Lineages from an HIV-1-Infected Individual

Krebs, Shelly J.; Kwon, Young Do; Schramm, Chaim A.; Law, William H.; Donofrio, G.; Zhou, Kenneth H.; Gift, Syna Kuriakose; Dussupt, Vincent; Georgiev, Ivelin S.; Schätzle, Sebastian; McDaniel, Jonathan R.; Lai, Yen‐Ting; Sastry, Mallika; Zhang, B.; Jarosinski, Marissa; Ransier, Amy; Chenine, Agnès‐Laurence; Asokan, Mangaiarkarasi; Bailer, Robert T.; Bose, Meera; Cagigi, Alberto; Cale, Evan M.; Chuang, Gwo-Yu; Darko, Samuel; Driscoll, Jefferson I; Druz, Aliaksandr; Gorman, Jason; Laboune, Farida; Louder, Mark K.; McKee, Krisha; Méndez, Lashly; Moody,; O’Sullivan, Anne Marie; Owen, Christopher L.; Peng, Dongjun; Rawi, Reda; Sanders‐Buell, Eric; Shen, Chen‐Hsiang; Shiakolas, Andrea R; Stephens, Tyler; Tsybovsky, Yaroslav; Tucker, Courtney; Verardi, Raffaello; Wang, K.; Zhou, Jing; Zhou, Tongqing; Georgiou, George; Alam, S. Munir; Haynes, Barton F.; Rolland, Morgane; Matyas, Gary R.; Polonis, Victoria R.; McDermott, Adrian B.; Douek, Daniel C.; Shapiro, Lawrence; Tovanabutra, Sodsai; Michael, N.L.; Mascola, John R.; Robb, Merlin L.; Kwong, Peter D.; Doria‐Rose, Nicole A.

doi:10.1016/j.immuni.2019.02.008

Cited by 88 publications

(122 citation statements)

References 90 publications

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“…Diverse mechanisms of antibody lineage development were found in chronic infection, especially in HIV studies. The initiation and early development of MPER-directed HIV antibody lineage have been reported to achieve high neutralizing breadth with low mutation from germline [53]. In a stark contrast, HIV-1 bNAbs VRC01 and PGT121, which target CD4 binding-site and V3 region respectively, require extensive mutation to achieve neutralizing breadth and potency and possess long HCDR3 loops to penetrate the glycan shield of the HIV-1 envelope spike [34, 44].…”

Section: Discussionmentioning

confidence: 99%

Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

Gao

Lin

et al. 2019

Preprint

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24Zika virus (ZIKV) specific neutralizing antibodies hold a great promise for 25 antibody-based interventions and vaccine design against ZIKV infection. 26 However, their development in infected patients remain unknown. Here, we 27 report on the dynamic development of a potent and protective ZIKV-specific 28 human antibody ZK2B10 initially isolated from a ZIKV convalescent individual 29 using next-generation sequencing (NGS). The unbiased repertoire analysis 30 showed dramatic changes in many families of heavy and light chain variable 31 regions. However, lineage tracing of ZK2B10 revealed limited somatic 32 hypermutation throughout the 12 months since the onset of symptom. In 33 particular, NGS-derived germline-like somatic variants neutralized and 34 protected mice from lethal challenge of ZIKV without detectable cross-reactivity 35 with Dengue virus (DENV). Site-directed mutagenesis identified two residues 36 within  chain, N31 and S91 that are essential to the functional maturation. The 37 dynamic features unveiled here will assist us to better understand the 38 pathogenesis of ZIKV infection and inform rational design of vaccines. 39Author summary 40 Recently emerged ZIKV is associated with severe neurological complications 41 such as Guillain-Barré syndrome in adults and congenital microcephaly in 42 newborns. No ZIKV-specific therapeutics or vaccines are currently available. 43 We and others have identified a number of neutralizing antibodies capable of 44 protecting experimental animals from ZIKV infection. However, the 3 45 development of these potent antibodies during ZIKV natural infection remains 46 unknown. Here, we report on the longitudinal analysis of one such antibody 47 ZK2B10 using next-generation sequencing (NGS), bioinformatics and 48 functional analysis. We found that the ZK2B10 germline-like antibodies 49 possess strong neutralizing activity in vitro and impressive protectivity against 50 lethal ZIKV infection in vivo. These findings suggest that the potent and 51 protective antibody response against ZIKV can be generated within relative 52 short term with high germline identity which provide great hope and promise for 53 successful vaccine development against ZIKV. 54 Key words 55 Zika virus infection, Guillain-Barré syndrome, microcephaly, neutralizing 56 antibody, antibody repertoire, next-generation sequencing 57 Introduction 58 Zika virus (ZIKV), a member of the Flavivirus genus of the Flaviviridae family, 59 is an emerging mosquito-borne pathogen. ZIKV is closely related to other 60 flavivirus such as dengue (DENV 1, 2, 3 and 4), yellow fever (YFV), West Nile 61 (WNV), Japanese encephalitis (JEV), and tick-borne encephalitis (TBEV) 62 viruses [1]. Since ZIKV was first identified in 1947 among rhesus macaques of 63 Uganda Zika forest, its new variants have become increasingly prevalent and 64 adapted to the human population as recent outbreaks have spread across the 65 Americas, Caribbean, and Southeast Asia [2-5]. At the peak of the 2016 4 66 outbreak, several incidents o...

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Section: Discussionmentioning

confidence: 99%

Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

Gao

Lin

et al. 2019

Preprint

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“…More recently, a new MPER targeting antibody lineage PGZL1 from donor PG13, and three lineages from donor RV-217 (VRC42, VRC43, VRC46) with outstanding breadth were discovered. These studies describe in more detail the maturation of MPER-targeting antibodies (Krebs et al, 2019), [Zhang, L. et. al. An MPER Antibody Neutralizes HIV-1 Using Germline Features Shared Among Donors.…”

Section: Introductionmentioning

confidence: 99%

“…These impressive bNAbs together with the high conservation of MPER sequence has stimulated renewed interest in MPER-targeting vaccine design and the use of MPER antibodies for postexposure prophylaxis. Crystal structures of many MPER Fabs have been solved, alone and in complex with MPER peptide and/or with additional short-tailed lipid headgroups (Irimia et al, 2016;Irimia et al, 2017;Krebs et al, 2019;Williams et al, 2017), [Zhang, L. et. al. An MPER Antibody Neutralizes HIV-1 Using Germline Features Shared Among Donors.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Envelope and MPER antibody structures in lipid assemblies

Rantalainen

Berndsen

Antanasijevic

et al. 2019

Preprint

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SummaryStructural and functional studies of HIV Env as a transmembrane protein have long been complicated by challenges associated with inherent flexibility of the molecule and the membrane-embedded hydrophobic regions. Thus, most structural studies have utilized soluble forms where the regions C-terminal to the ectodomain are deleted. Here, we present approaches for incorporating full-length, wild-type HIV-1 Env, as well as C-terminally truncated and stabilized versions, into lipid assemblies, providing a modular platform for Env structural studies by single particle electron microscopy. We reconstituted a full-length Env clone into a nanodisc with MSP1D1 scaffold, complexed it with an MPER targeting antibody 10E8, and structurally defined the full quaternary epitope of 10E8 consisting of lipid, MPER and ectodomain contacts. By aligning this and other Env-MPER antibody complex reconstructions with the lipid bilayer, we observe evidence of Env tilting as part of the neutralization mechanism for MPER-targeting antibodies. We also adapted the platform toward vaccine design purposes by introducing stabilizing mutations that allow purification of unliganded Env with peptidisc scaffold.

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“…Diverse mechanisms of antibody lineage development have been found in chronic infections. During HIV-1 infection, rapidly emerged MPERdirected antibody lineages have been reported to achieve neutralizing breadth with low levels of SHM (55). In contrast, HIV-1 bNAbs VRC01 and PGT121, which target the CD4 binding site (CD4bs) and the V3 stem, respectively, require extensive mutation to achieve neutralizing breadth and potency (34,36).…”

Section: Discussionmentioning

confidence: 99%

Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human

Gao

Lin

et al. 2019

Front. Immunol.

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Zika virus (ZIKV) specific neutralizing antibodies hold great promise for antibody-based interventions and vaccine design against ZIKV infection. However, their development in infected patients remains unclear. Here, we applied next-generation sequencing (NGS) to probe the dynamic development of a potent and protective ZIKV E DIII-specific antibody ZK2B10 isolated from a ZIKV convalescent individual. The unbiased repertoire analysis showed dramatic changes in the usage of antibody variable region germline genes. However, lineage tracing of ZK2B10 revealed limited somatic hypermutation and transient expansion during the 12 months following the onset of symptoms. The NGS-derived, germline-like ZK2B10 somatic variants neutralized ZIKV potently and protected mice from lethal challenge of ZIKV without detectable cross-reactivity with Dengue virus (DENV). Site-directed mutagenesis identified two residues within the λ chain, N31 and S91, that are essential to the functional maturation of ZK2B10. The repertoire and lineage features unveiled here will help elucidate the developmental process and protective potential of E DIII-directed antibodies against ZIKV infection.

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Longitudinal Analysis Reveals Early Development of Three MPER-Directed Neutralizing Antibody Lineages from an HIV-1-Infected Individual

Cited by 88 publications

References 90 publications

Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

Development of a potent and protective germline-like antibody lineage against Zika virus in a convalescent human

HIV-1 Envelope and MPER antibody structures in lipid assemblies

Development of a Potent and Protective Germline-Like Antibody Lineage Against Zika Virus in a Convalescent Human

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