Rhesus and cynomolgus macaque immunoglobulin heavy-chain genotyping yields comprehensive databases of germline VDJ alleles

Bernat, Néstor Vázquez; Corcoran, Martin; Nowak, Izabela; Kaduk, Mateusz; Dopico, Xaquín Castro; Narang, Sanjana; Maisonasse, Pauline; Dereuddre‐Bosquet, Nathalie; Murrell, Ben; Hedestam, Gunilla B. Karlsson

doi:10.1016/j.immuni.2020.12.018

Cited by 65 publications

(117 citation statements)

References 45 publications

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“…D20-isolated mAbs are clonally related and use the VH4.11_S9546, JH 5–1*01_S8786, lib4kappa_12 and JK2*01 or JK4*01 germline genes [ 26 ] ( Fig 1E ). The somatic hyper mutation (SHM) levels in VH and VL range from 4.2–17.5% and 3.1–11.1% at the residue (aa) level, respectively ( Fig 1E ) [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization

et al. 2021

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Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 μg/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184–186) that is unique to the 16055 strain. They also provide potential explanations for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.

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Section: Resultsmentioning

confidence: 99%

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization

et al. 2021

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“…Despite the fact that the Ig loci of natural outbred organisms are known to be extremely diverse, much of our understanding of the mechanisms dictating V(D)J recombination have come from studies of inbred models. However, even in inbred models, it has been demonstrated that Ig genetic diversity is more extensive than initially appreciated, in many cases mirroring (or even exceeding) what has been observed in human populations and other more outbred organisms (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). In mouse, for example, a comparison of germline V H sequences between C57BL/6 and BALB/c revealed surprisingly little overlap in the germline repertoires of these two strains.…”

Section: The V H Gene Usage Conundrummentioning

confidence: 98%

Igh Locus Polymorphism May Dictate Topological Chromatin Conformation and V Gene Usage in the Ig Repertoire

2021

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Vast repertoires of unique antigen receptors are created in developing B and T lymphocytes. The antigen receptor loci contain many variable (V), diversity (D) and joining (J) gene segments that are arrayed across very large genomic expanses and are joined to form variable-region exons of expressed immunoglobulins and T cell receptors. This process creates the potential for an organism to respond to large numbers of different pathogens. Here, we consider the possibility that genetic polymorphisms with alterations in a vast array of regulatory elements in the immunoglobulin heavy chain (IgH) locus lead to changes in locus topology and impact immune-repertoire formation.

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“…We used single memory B cell sorting to isolate mAbs from animals that showed the highest serum [26] (Fig 1E). The somatic hyper mutation (SHM) levels in VH and VL range from 4.2-16.7% and 3.1-11.1% at the residue (aa) level, respectively (Fig 1E) [27].…”

Section: Fig)mentioning

confidence: 99%

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization

Aljedani

Liban

Tran

et al. 2021

Preprint

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Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 ug/ml (IC 50 ). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a β-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide an explanation for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies.

show abstract

Rhesus and cynomolgus macaque immunoglobulin heavy-chain genotyping yields comprehensive databases of germline VDJ alleles

Cited by 65 publications

References 45 publications

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization

Igh Locus Polymorphism May Dictate Topological Chromatin Conformation and V Gene Usage in the Ig Repertoire

Structurally related but genetically unrelated antibody lineages converge on an immunodominant HIV-1 Env neutralizing determinant following trimer immunization

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