Tuning environmental timescales to evolve and maintain generalists

Natural environments can present diverse challenges, but some genotypes remain fit across many environments. Such “generalists” can be hard to evolve, outcompeted by specialists fitter in any particular environment. Here, inspired by the search for broadly neutralizing antibodies during B cell affinity maturation, we demonstrate that environmental changes on an intermediate timescale can reliably evolve generalists, even when faster or slower environmental changes are unable to do so. We find that changing environments on timescales comparable with evolutionary transients in a population enhance the rate of evolving generalists from specialists, without enhancing the reverse process. The yield of generalists is further increased in more complex dynamic environments, such as a “chirp” of increasing frequency. Our work offers design principles for how nonequilibrium fitness “seascapes” can dynamically funnel populations to genotypes unobtainable in static environments.

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Multiscale affinity maturation simulations to elicit HIV broadly neutralizing antibodies

10.1101/2021.09.01.458482 ◽

2021 ◽

Author(s):

Kayla Sprenger ◽

Simone Conti ◽

Victor Ovchinnikov ◽

Arup K Chakraborty ◽

martin karplus

Keyword(s):

Neutralizing Antibodies ◽

Adaptive Immune System ◽

Multiscale Model ◽

Cell Receptor ◽

Affinity Maturation ◽

Sequencing Data ◽

Broadly Neutralizing Antibodies ◽

Adaptive Immune ◽

Cd4 Binding Site ◽

Anti Hiv

The design of vaccines against highly mutable pathogens, such as HIV and influenza, requires a detailed understanding of how the adaptive immune system responds to encountering multiple variant antigens (Ags). Here, we describe a multiscale model of B cell receptor (BCR) affinity maturation that employs actual BCR nucleotide sequences and treats BCR/Ag interactions in atomistic detail. We apply the model to simulate the maturation of a broadly neutralizing Ab (bnAb) against HIV. Starting from a germline precursor sequence of the VRC01 anti-HIV Ab, we simulate BCR evolution in response to different vaccination protocols and different Ags, which were previously designed by us. The simulation results provide qualitative guidelines for future vaccine design and reveal unique insights into bnAb evolution against the CD4 binding site of HIV. Our model makes possible direct comparisons of simulated BCR populations with results of deep sequencing data, which will be explored in future applications.

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Role of framework mutations and antibody flexibility in the evolution of broadly neutralizing antibodies

eLife ◽

10.7554/elife.33038 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 25

Author(s):

Victor Ovchinnikov ◽

Joy E Louveau ◽

John P Barton ◽

Martin Karplus ◽

Arup K Chakraborty

Keyword(s):

B Cells ◽

Neutralizing Antibodies ◽

Affinity Maturation ◽

Surface Proteins ◽

Initial Increase ◽

Broadly Neutralizing Antibodies ◽

Rigidity Result ◽

Conserved Residues ◽

Immunogen Design ◽

Dynamics Simulations

Eliciting antibodies that are cross reactive with surface proteins of diverse strains of highly mutable pathogens (e.g., HIV, influenza) could be key for developing effective universal vaccines. Mutations in the framework regions of such broadly neutralizing antibodies (bnAbs) have been reported to play a role in determining their properties. We used molecular dynamics simulations and models of affinity maturation to study specific bnAbs against HIV. Our results suggest that there are different classes of evolutionary lineages for the bnAbs. If germline B cells that initiate affinity maturation have high affinity for the conserved residues of the targeted epitope, framework mutations increase antibody rigidity as affinity maturation progresses to evolve bnAbs. If the germline B cells exhibit weak/moderate affinity for conserved residues, an initial increase in flexibility via framework mutations may be required for the evolution of bnAbs. Subsequent mutations that increase rigidity result in highly potent bnAbs. Implications of our results for immunogen design are discussed.

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Dominance patterns in dynamic environments

10.1101/2020.02.25.965103 ◽

2020 ◽

Author(s):

Archana Devi ◽

Kavita Jain

Keyword(s):

Environmental Change ◽

Dynamic Environments ◽

Natural Environments ◽

Phase Lag ◽

Fixation Probability ◽

Diploid Population ◽

Changing Environment ◽

Changing Environments ◽

Recurrent Mutations ◽

Varying Environment

AbstractNatural environments are seldom static and therefore it is important to ask how a population adapts in a changing environment. We consider a finite, diploid population with intermediate dominance evolving in a periodically changing environment and study how the fixation probability of a rare mutant depends on its dominance coefficient and the rate of environmental change. We find that in slowly changing environments, the dominance patterns are the same as in the static environment, that is, if a mutant is beneficial (deleterious) when it arrives, it is more (less) likely to fix if it is dominant. But in fast changing environments, these patterns depend on the mutant’s fitness on arrival as well as that in the time-averaged environment. We find that in a rapidly varying environment that is neutral or deleterious on-average, an initially beneficial (deleterious) mutant that arises while selection is decreasing (increasing) has a fixation probability lower (higher) than that for a neutral mutant leading to a reversal in the standard dominance patterns. We also find that recurrent mutations decrease the phase lag between the environment and the allele frequency, irrespective of the level of dominance.

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Structure of the apo anti-influenza CH65 Fab

Acta Crystallographica Section F Structural Biology Communications ◽

10.1107/s2053230x14027599 ◽

2015 ◽

Vol 71 (2) ◽

pp. 145-148 ◽

Cited By ~ 2

Author(s):

Peter S. Lee ◽

Ashley J. Arnell ◽

Ian A. Wilson

Keyword(s):

Neutralizing Antibodies ◽

Affinity Maturation ◽

Influenza Viruses ◽

Antigenic Drift ◽

Human Antibody ◽

Broadly Neutralizing Antibodies ◽

High Affinity ◽

Influenza Hemagglutinin ◽

Universal Influenza Vaccine ◽

Complementarity Determining Region

Influenza viruses remain a persistent challenge to human health owing to their inherent ability to evade the immune response by antigenic drift. However, the discovery of broadly neutralizing antibodies (bnAbs) against divergent viruses has sparked renewed interest in a universal influenza vaccine and novel therapeutic opportunities. Here, a crystal structure at 1.70 Å resolution is presented of the Fab of the human antibody CH65, which has broad neutralizing activity against a range of seasonal H1 isolates. Previous studies proposed that affinity maturation of this antibody lineage pre-organizes the complementarity-determining region (CDR) loops into an energetically favorable HA-bound conformation. Indeed, from the structural comparisons of free and HA-bound CH65 presented here, the CDR loops, and in particular the heavy-chain CDR3, adopt the same conformations in the free and bound forms. Thus, these findings support the notion that affinity maturation of the CH65 lineage favorably preconfigures the CDR loops for high-affinity binding to influenza hemagglutinin.

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Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1709203114 ◽

2017 ◽

Vol 114 (32) ◽

pp. 8614-8619 ◽

Cited By ~ 21

Author(s):

Joyce K. Hwang ◽

Chong Wang ◽

Zhou Du ◽

Robin M. Meyers ◽

Thomas B. Kepler ◽

...

Keyword(s):

B Cells ◽

Neutralizing Antibodies ◽

Somatic Hypermutation ◽

Human Subjects ◽

Variable Region ◽

Affinity Maturation ◽

Broadly Neutralizing Antibodies ◽

Variable Regions ◽

Complementarity Determining Regions ◽

Hiv 1

Variable regions of Ig chains provide the antigen recognition portion of B-cell receptors and derivative antibodies. Ig heavy-chain variable region exons are assembled developmentally from V, D, J gene segments. Each variable region contains three antigen-contacting complementarity-determining regions (CDRs), with CDR1 and CDR2 encoded by the V segment and CDR3 encoded by the V(D)J junction region. Antigen-stimulated germinal center (GC) B cells undergo somatic hypermutation (SHM) of V(D)J exons followed by selection for SHMs that increase antigen-binding affinity. Some HIV-1–infected human subjects develop broadly neutralizing antibodies (bnAbs), such as the potent VRC01-class bnAbs, that neutralize diverse HIV-1 strains. Mature VRC01-class bnAbs, including VRC-PG04, accumulate very high SHM levels, a property that hinders development of vaccine strategies to elicit them. Because many VRC01-class bnAb SHMs are not required for broad neutralization, high overall SHM may be required to achieve certain functional SHMs. To elucidate such requirements, we used a V(D)J passenger allele system to assay, in mouse GC B cells, sequence-intrinsic SHM-targeting rates of nucleotides across substrates representing maturation stages of human VRC-PG04. We identify rate-limiting SHM positions for VRC-PG04 maturation, as well as SHM hotspots and intrinsically frequent deletions associated with SHM. We find that mature VRC-PG04 has low SHM capability due to hotspot saturation but also demonstrate that generation of new SHM hotspots and saturation of existing hotspot regions (e.g., CDR3) does not majorly influence intrinsic SHM in unmutated portions of VRC-PG04 progenitor sequences. We discuss implications of our findings for bnAb affinity maturation mechanisms.

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Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies

Journal of Experimental Medicine ◽

10.1084/jem.20122824 ◽

2013 ◽

Vol 210 (4) ◽

pp. 655-663 ◽

Cited By ~ 195

Author(s):

Andrew T. McGuire ◽

Sam Hoot ◽

Anita M. Dreyer ◽

Adriana Lippy ◽

Andrew Stuart ◽

...

Keyword(s):

Binding Site ◽

Neutralizing Antibodies ◽

Variable Region ◽

Neutralizing Antibody ◽

Glycosylation Site ◽

Affinity Maturation ◽

Broadly Neutralizing Antibodies ◽

Cd4 Binding Site ◽

Broadly Neutralizing Antibody ◽

Hiv Envelope

Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.

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Quantifying the effects of single mutations on viral escape from broad and narrow antibodies to an H1 influenza hemagglutinin

10.1101/210468 ◽

2017 ◽

Cited By ~ 1

Author(s):

Michael B. Doud ◽

Juhye M. Lee ◽

Jesse D. Bloom

Keyword(s):

Influenza Virus ◽

Neutralizing Antibodies ◽

Viral Escape ◽

Effect Sizes ◽

Single Amino Acid ◽

Broadly Neutralizing Antibodies ◽

Receptor Binding Site ◽

Influenza Hemagglutinin ◽

Amino Acid Mutations ◽

Do So

ABSTRACTInfluenza virus can completely escape most antibodies with single mutations. However, rare antibodies broadly neutralize many viral strains. It is unclear how easily influenza virus might escape such antibodies if it was under strong pressure to do so. Here we map all single amino-acid mutations that increase resistance to broad antibodies targeting an H1 hemagglutinin. Crucially, our approach not only identifies antigenic mutations but also quantifies their effect sizes. All antibodies select mutations, but the effect sizes vary widely. The virus can escape a broad antibody that targets residues in hemagglutinin’s receptor-binding site the same way it escapes narrow strain-specific antibodies: via single mutations with huge effects. In contrast, broad antibodies targeting hemagglutinin’s stalk only select mutations with small effects. Therefore, among the antibodies we have examined, breadth is an imperfect indicator of the potential for viral escape via single mutations. Broadly neutralizing antibodies targeting the H1 hemagglutinin stalk are quantifiably harder to escape than the other antibodies tested here.

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Injection of antibodies against immunodominant epitopes tunes germinal centres to generate broadly neutralizing antibodies

10.1101/501247 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michael Meyer-Hermann

Keyword(s):

Neutralizing Antibodies ◽

Feedback Loop ◽

Viral Infections ◽

Affinity Maturation ◽

Small Subset ◽

Broadly Neutralizing Antibodies ◽

Germinal Centres ◽

Life Threatening ◽

Design And Testing ◽

Immunodominant Epitopes

The development of broadly neutralizing antibodies is critical for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Elite neutralizers are generated by natural germinal centre (GC) reactions in a very small subset of patients. The best strategy of how to promote the generation of broadly neutralizing antibodies is not known. Here, computer simulations of GC reactions are used to predict a feedback loop based on memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. The simulations suggest that the injection of antibodies against immunodominant epitopes fosters affinity maturation of antibodies specific for rare or hidden epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.

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Evolving Learnable Neural Networks Under Changing Environments with Various Rates of Inheritance of Acquired Characters: Comparison of Darwinian and Lamarckian Evolution

Artificial Life ◽

10.1162/106454699568746 ◽

1999 ◽

Vol 5 (3) ◽

pp. 203-223 ◽

Cited By ~ 14

Author(s):

Takahiro Sasaki ◽

Mario Tokoro

Keyword(s):

Neural Networks ◽

Environmental Changes ◽

Dynamic Environments ◽

Abstract Model ◽

Changing Environments ◽

Lamarckian Evolution ◽

Inheritance Of Acquired Characters ◽

Acquired Characters ◽

Successive Generations ◽

The Relationship

The processes of adaptation in natural organisms consist of two complementary phases: learning, occurring within each individual's lifetime, and evolution, occurring over successive generations of the population. In this article, we study the relationship between learning and evolution in a simple abstract model, where neural networks capable of learning are evolved using genetic algorithms (GAs). Individuals try to maximize their life energy by learning certain rules that distinguish between two groups of materials: food and poison. The connective weights of individuals' neural networks undergo modification, that is, certain characters will be acquired, through their lifetime learning. By setting various rates for the heritability of acquired characters, which is a motive force of Lamarckian evolution, we observe adaptational processes of populations over successive generations. Paying particular attention to behaviors under changing environments, we show the following results. Populations with lower rates of heritability not only show more stable behavior against environmental changes, but also maintain greater adaptability with respect to such changing environments. Consequently, the population with zero heritability, that is, the Darwinian population, attains the highest level of adaptation to dynamic environments.

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Mechanisms underlying vaccination protocols that may optimally elicit broadly neutralizing antibodies against highly mutable pathogens

10.1101/2020.10.07.330340 ◽

2020 ◽

Author(s):

Raman S. Ganti ◽

Arup K. Chakraborty

Keyword(s):

B Cells ◽

B Cell ◽

Cell Population ◽

Neutralizing Antibodies ◽

Population Distribution ◽

Fitness Landscape ◽

Affinity Maturation ◽

Host Cells ◽

Time Varying ◽

Broadly Neutralizing Antibodies

Effective prophylactic vaccines usually induce the immune system to generate potent antibodies that can bind to an antigen and thus prevent it from infecting host cells. B cells produce antibodies by a Darwinian evolutionary process called affinity maturation (AM). During AM, the B cell population evolves in response to the antigen. Antibodies that bind specifically and strongly to the antigen are thus produced. Highly mutable pathogens pose a major challenge to the development of effective vaccines because antibodies that are effective against one strain of the virus may not protect against a mutant strain. Antibodies that can protect against diverse strains of a mutable pathogen are called broadly neutralizing antibodies (bnAbs). In spite of extensive experimental and computational studies that have led to important advances, an effective vaccination strategy that can generate bnAbs does not exist for any highly mutable pathogen. Here we study a minimal model of AM in different time-varying antigenic environments to explore the mechanisms underlying optimal vaccination protocols that maximize the production of bnAbs. We find that the characteristics of the time-varying Kullback-Leibler distance (KLD) between the B cell population distribution and the fitness landscape imposed by antigens is a key determinant of bnAb evolution. The optimal vaccination protocol requires a relatively low KLD in the beginning in order to increase the entropy (diversity) of the B cell population so that the surviving B cells have a high chance of evolving into bnAbs upon subsequently increasing the KLD. For a discretized two-step variation in antigenic environment, there are optimal values of the KLDs for the first and second steps. Phylogenetic tree analysis further reveals the evolutionary pathways that lead to bnAbs. The connections between our results and recent simulation studies of bnAb evolution and the general problem of evolution of generalists versus specialists are discussed.

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