scholarly journals Modelling the Decay of Hotspot Motifs in Broadly Neutralizing Antibody Lineages

2016 ◽  
Author(s):  
Kenneth B Hoehn ◽  
Gerton Lunter ◽  
Oliver G Pybus
Keyword(s):  
Somatic Hypermutation ◽  
Neutralizing Antibody ◽  
Context Dependency ◽  
Great Promise ◽  
Ancestral State ◽  
Substitution Model ◽  
Phylogenetic Methods ◽  
Broadly Neutralizing Antibody ◽  
Type Substitution ◽  
Mutational Process

AbstractPhylogenetic methods have shown great promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, mutational process for generating these lineages - somatic hypermutation (SHM) - is biased by hotspot motifs, which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model which partially accounts for this context-dependency while preserving independence of sites in calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We show through simulations that accounting for this can lead to reduced bias of other substitution parameters, and more accurate ancestral state reconstructions. We further explore other implications of this model; namely, that the number of hotspot motifs - and therefore likely the mutation rate in general - is expected to decay over time in individual bNAb lineages.

scholarly journals A phylogenetic codon substitution model for antibody lineages

2016 ◽  
Author(s):  
Kenneth B Hoehn ◽  
Gerton Lunter ◽  
Oliver G Pybus
Keyword(s):  
Somatic Hypermutation ◽  
Neutralizing Antibody ◽  
Context Dependency ◽  
Ancestral State ◽  
Substitution Model ◽  
Codon Substitution ◽  
Codon Substitution Model ◽  
Broadly Neutralizing Antibody ◽  
Type Substitution ◽  
Mutational Process

AbstractPhylogenetic methods have shown promise in understanding the development of broadly neutralizing antibody lineages (bNAbs). However, the mutational process that generates these lineages – somatic hypermutation (SHM) – is biased by hotspot motifs, which violates important assumptions in most phylogenetic substitution models. Here, we develop a modified GY94-type substitution model that partially accounts for this context-dependency while preserving independence of sites during calculation. This model shows a substantially better fit to three well-characterized bNAb lineages than the standard GY94 model. We show through simulations that accounting for hotspot motifs can lead to reduced bias of other substitution parameters, and more accurate ancestral state reconstructions. We also demonstrate how our model can be used to test hypotheses concerning the roles of different hotspot and coldspot motifs in the evolution of B-cell lineages. Further, we explore the consequences of the idea that the number of hotspot motifs – and perhaps the mutation rate in general – is expected to decay over time in individual bNAb lineages.

scholarly journals Mutational fitness landscapes reveal genetic and structural improvement pathways for a vaccine-elicited HIV-1 broadly neutralizing antibody

2021 ◽  
Vol 118 (10) ◽  
pp. e2011653118
Author(s):  
Bharat Madan ◽  
Baoshan Zhang ◽  
Kai Xu ◽  
Cara W. Chao ◽  
Sijy O’Dell ◽  
...  
Keyword(s):  
Conformational Dynamics ◽  
Neutralizing Antibody ◽  
Saturation Mutagenesis ◽  
Great Promise ◽  
Functional Screening ◽  
Viral Neutralization ◽  
Mutational Landscape ◽  
Broadly Neutralizing Antibody ◽  
Functional Features ◽  
Hiv 1

Vaccine-based elicitation of broadly neutralizing antibodies holds great promise for preventing HIV-1 transmission. However, the key biophysical markers of improved antibody recognition remain uncertain in the diverse landscape of potential antibody mutation pathways, and a more complete understanding of anti–HIV-1 fusion peptide (FP) antibody development will accelerate rational vaccine designs. Here we survey the mutational landscape of the vaccine-elicited anti-FP antibody, vFP16.02, to determine the genetic, structural, and functional features associated with antibody improvement or fitness. Using site-saturation mutagenesis and yeast display functional screening, we found that 1% of possible single mutations improved HIV-1 envelope trimer (Env) affinity, but generally comprised rare somatic hypermutations that may not arise frequently in vivo. We observed that many single mutations in the vFP16.02 Fab could enhance affinity >1,000-fold against soluble FP, although affinity improvements against the HIV-1 trimer were more measured and rare. The most potent variants enhanced affinity to both soluble FP and Env, had mutations concentrated in antibody framework regions, and achieved up to 37% neutralization breadth compared to 28% neutralization of the template antibody. Altered heavy- and light-chain interface angles and conformational dynamics, as well as reduced Fab thermal stability, were associated with improved HIV-1 neutralization breadth and potency. We also observed parallel sets of mutations that enhanced viral neutralization through similar structural mechanisms. These data provide a quantitative understanding of the mutational landscape for vaccine-elicited FP-directed broadly neutralizing antibody and demonstrate that numerous antigen-distal framework mutations can improve antibody function by enhancing affinity simultaneously toward HIV-1 Env and FP.

scholarly journals Myomedin scaffold variants targeted to 10E8 HIV-1 broadly neutralizing antibody mimic gp41 epitope and elicit HIV-1 virus-neutralizing sera in mice

Virulence ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 1271-1287
Author(s):  
Milan Kuchař ◽  
Petr Kosztyu ◽  
Veronika Daniel Lišková ◽  
Jiří Černý ◽  
Hana Petroková ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

scholarly journals HIV mRNA Vaccines—Progress and Future Paths

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 134
Author(s):  
Zekun Mu ◽  
Barton F. Haynes ◽  
Derek W. Cain
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccination Strategy ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cytotoxic T Cell ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Broadly Neutralizing Antibody ◽  
Cytotoxic T Cell Responses

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

scholarly journals HIV broadly neutralizing antibody targets

2015 ◽  
Vol 10 (3) ◽  
pp. 135-143 ◽  
Author(s):  
Constantinos Kurt Wibmer ◽  
Penny L. Moore ◽  
Lynn Morris
Keyword(s):  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibody
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