Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies.

Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope.

How persistent infection overcomes peripheral tolerance mechanisms to cause T cell-mediated autoimmune disease.

T cells help orchestrate immune responses to pathogens, and their aberrant regulation can trigger autoimmunity. Recent studies highlight that a threshold number of T cells (a quorum) must be activated in a tissue to mount a functional immune response. These collective effects allow the T cell repertoire to respond to pathogens while suppressing autoimmunity due to circulating autoreactive T cells. Our computational studies show that increasing numbers of pathogenic peptides targeted by T cells during persistent or severe viral infections increase the probability of activating T cells that are weakly reactive to self-antigens (molecular mimicry). These T cells are easily re-activated by the self-antigens and contribute to exceeding the quorum threshold required to mount autoimmune responses. Rare peptides that activate many T cells are sampled more readily during severe/persistent infections than in acute infections, which amplifies these effects. Experiments in mice to test predictions from these mechanistic insights are suggested.

Polymer folding through active processes recreates features of genome organization.

From proteins to chromosomes, polymers fold into specific conformations that control their biological function. Polymer folding has long been studied with equilibrium thermodynamics, yet intracellular organization and regulation involve energy-consuming, active processes. Signatures of activity have been measured in the context of chromatin motion, which shows spatial correlations and enhanced subdiffusion only in the presence of adenosine triphosphate. Moreover, chromatin motion varies with genomic coordinate, pointing toward a heterogeneous pattern of active processes along the sequence. How do such patterns of activity affect the conformation of a polymer such as chromatin? We address this question by combining analytical theory and simulations to study a polymer subjected to sequence-dependent correlated active forces. Our analysis shows that a local increase in activity (larger active forces) can cause the polymer backbone to bend and expand, while less active segments straighten out and condense. Our simulations further predict that modest activity differences can drive compartmentalization of the polymer consistent with the patterns observed in chromosome conformation capture experiments. Moreover, segments of the polymer that show correlated active (sub)diffusion attract each other through effective long-ranged harmonic interactions, whereas anticorrelations lead to effective repulsions. Thus, our theory offers nonequilibrium mechanisms for forming genomic compartments, which cannot be distinguished from affinity-based folding using structural data alone. As a first step toward exploring whether active mechanisms contribute to shaping genome conformations, we discuss a data-driven approach.

Scale-Dependent Heat Transport in Dissipative Media via Electromagnetic Fluctuations.

We develop a theory for heat transport via electromagnetic waves inside media, and use it to derive a spatially nonlocal thermal conductivity tensor, in terms of the electromagnetic Green's function and potential, for any given system. While typically negligible for optically dense bulk media, the electromagnetic component of conductivity can be significant for optically dilute media, and shows regimes of Fourier transport as well as unhindered transport. Moreover, the electromagnetic contribution is relevant even for dense media, when in the presence of interfaces, as exemplified for the in-plane conductivity of a nanosheet, which shows a variety of phenomena, including absence of a Fourier regime.

Disorder-Induced Long-Ranged Correlations in Scalar Active Matter.

We study the impact of quenched random potentials and torques on scalar active matter. Microscopic simulations reveal that motility-induced phase separation is replaced in two dimensions by an asymptotically homogeneous phase with anomalous long-ranged correlations and nonvanishing steady-state currents. Using a combination of phenomenological models and a field-theoretical treatment, we show the existence of a lower-critical dimension d_{c}=4, below which phase separation is only observed for systems smaller than an Imry-Ma length scale. We identify a weak-disorder regime in which the structure factor scales as S(q)∼1/q^{2}, which accounts for our numerics. In d=2, we predict that, at larger scales, the behavior should cross over to a strong-disorder regime. In d>2, these two regimes exist separately, depending on the strength of the potential.

Near Field Propulsion Forces from Nonreciprocal Media.

Arguments based on symmetry and thermodynamics may suggest the existence of a ratchetlike lateral Casimir force between two plates at different temperatures and with broken inversion symmetry. We find that this is not sufficient, and at least one plate must be made of nonreciprocal material. This setup operates as a heat engine by transforming heat radiation into mechanical force. Although the ratio of the lateral force to heat transfer in the near field regime diverges inversely with the plates separation, d, an Onsager symmetry, which we extend to nonreciprocal plates, limits the engine efficiency to the Carnot value η_{c}. The optimal velocity of operation in the far field is of the order of cη_{c}, where c is the speed of light. In the near field regime, this velocity can be reduced to the order of ω[over ¯]dη_{c}, where ω[over ¯] is a typical material frequency.

Active motion of passive asymmetric dumbbells in a non-equilibrium bath.

Persistent motion of passive asymmetric bodies in non-equilibrium media has been experimentally observed in a variety of settings. However, fundamental constraints on the efficiency of such motion are not fully explored. Understanding such limits, and ways to circumvent them, is important for efficient utilization of energy stored in agitated surroundings for purposes of taxis and transport. Here, we examine such issues in the context of erratic movements of a passive asymmetric dumbbell driven by non-equilibrium noise. For uncorrelated (white) noise, we find a (non-Boltzmann) joint probability distribution for the velocity and orientation, which indicates that the dumbbell preferentially moves along its symmetry axis. The dumbbell thus behaves as an Ornstein-Uhlenbeck walker, a prototype of active matter. Exploring the efficiency of this active motion, we show that in the over-damped limit, the persistence length l of the dumbbell is bound from above by half its mean size, while the propulsion speed v∥ is proportional to its inverse size. The persistence length can be increased by exploiting inertial effects beyond the over-damped regime, but this improvement always comes at the price of smaller propulsion speeds. This limitation is explained by noting that the diffusivity of a dumbbell, related to the product v∥l, is always less than that of its components, thus severely constraining the usefulness of passive dumbbells as active particles.

Activated diffusiophoresis.

Perturbations of fluid media can give rise to non-equilibrium dynamics, which may, in turn, cause motion of immersed inclusions or tracer particles. We consider perturbations ("activations") that are local in space and time, of a fluid density which is conserved, and study the resulting diffusiophoretic phenomena that emerge at a large distance. Specifically, we consider cases where the perturbations propagate diffusively, providing examples from passive and active matter for which this is expected to be the case. Activations can, for instance, be realized by sudden and local changes in interaction potentials of the medium or by local changes in its activity. Various analytical results are provided for the case of confinement by two parallel walls. We investigate the possibility of extracting work from inclusions, which are moving through the activated fluid. Furthermore, we show that a time-dependent density profile, created via suitable activation protocols, allows for the conveyance of inclusions along controlled and stable trajectories. In contrast, in states with a steady density, inclusions cannot be held at stable positions, reminiscent of Earnshaw's theorem of electrostatics. We expect these findings to be applicable in a range of experimental systems. The phenomena described here are argued to be distinct from other forms of phoresis such as thermophoresis.

Publisher's Note: Transient Casimir Forces from Quenches in Thermal and Active Matter [Phys. Rev. Lett. 118, 015702 (2017)].

This corrects the article DOI: 10.1103/PhysRevLett.118.015702.

Evolution in range expansions with competition at rough boundaries.

When a biological population expands into new territory, genetic drift develops an enormous influence on evolution at the propagating front. In such range expansion processes, fluctuations in allele frequencies occur through stochastic spatial wandering of both genetic lineages and the boundaries between genetically segregated sectors. Laboratory experiments on microbial range expansions have shown that this stochastic wandering, transverse to the front, is superdiffusive due to the front's growing roughness, implying much faster loss of genetic diversity than predicted by simple flat front diffusive models. We study the evolutionary consequences of this superdiffusive wandering using two complementary numerical models of range expansions: the stepping stone model, and a new interpretation of the model of directed paths in random media, in the context of a roughening population front. Through these approaches we compute statistics for the times since common ancestry for pairs of individuals with a given spatial separation at the front, and we explore how environmental heterogeneities can locally suppress these superdiffusive fluctuations.

The low spike density of HIV may have evolved because of the effects of T helper cell depletion on affinity maturation.

The spikes on virus surfaces bind receptors on host cells to propagate infection. High spike densities (SDs) can promote infection, but spikes are also targets of antibody-mediated immune responses. Thus, diverse evolutionary pressures can influence virus SDs. HIV's SD is about two orders of magnitude lower than that of other viruses, a surprising feature of unknown origin. By modeling antibody evolution through affinity maturation, we find that an intermediate SD maximizes the affinity of generated antibodies. We argue that this leads most viruses to evolve high SDs. T helper cells, which are depleted during early HIV infection, play a key role in antibody evolution. We find that T helper cell depletion results in high affinity antibodies when SD is high, but not if SD is low. This special feature of HIV infection may have led to the evolution of a low SD to avoid potent immune responses early in infection.

Pair dispersion in dilute suspension of active swimmers.

Ensembles of biological and artificial microswimmers produce long-range velocity fields with strong nonequilibrium fluctuations, which result in a dramatic increase in diffusivity of embedded particles (tracers). While such enhanced diffusivity may point to enhanced mixing of the fluid, a rigorous quantification of the mixing efficiency requires analysis of pair dispersion of tracers, rather than simple one-particle diffusivity. Here, we calculate analytically the scale-dependent coefficient of relative diffusivity of passive tracers embedded in a dilute suspension of run-and-tumble microswimmers. Although each tracer is subject to strong fluctuations resulting in large absolute diffusivity, the small-scale relative dispersion is suppressed due to the correlations in fluid velocity which are relevant when the inter-tracer separation is below the persistence length of the swimmer's motion. Our results suggest that the reorientation of swimming direction plays an important role in biological mixing and should be accounted in the design of potential active matter devices capable of effective fluid mixing at microscale.

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens.

Strategies to elicit Abs that can neutralize diverse strains of a highly mutable pathogen are likely to result in a potent vaccine. Broadly neutralizing Abs (bnAbs) against HIV have been isolated from patients, proving that the human immune system can evolve them. Using computer simulations and theory, we study immunization with diverse mixtures of variant antigens (Ags). Our results show that particular choices for the number of variant Ags and the mutational distances separating them maximize the probability of inducing bnAbs. The variant Ags represent potentially conflicting selection forces that can frustrate the Darwinian evolutionary process of affinity maturation. An intermediate level of frustration maximizes the chance of evolving bnAbs. A simple model makes vivid the origin of this principle of optimal frustration. Our results, combined with past studies, suggest that an appropriately chosen permutation of immunization with an optimally designed mixture (using the principles that we describe) and sequential immunization with variant Ags that are separated by relatively large mutational distances may best promote the evolution of bnAbs.

Scaling laws describe memories of host-pathogen riposte in the HIV population.

The enormous genetic diversity and mutability of HIV has prevented effective control of this virus by natural immune responses or vaccination. Evolution of the circulating HIV population has thus occurred in response to diverse, ultimately ineffective, immune selection pressures that randomly change from host to host. We show that the interplay between the diversity of human immune responses and the ways that HIV mutates to evade them results in distinct sets of sequences defined by similar collectively coupled mutations. Scaling laws that relate these sets of sequences resemble those observed in linguistics and other branches of inquiry, and dynamics reminiscent of neural networks are observed. Like neural networks that store memories of past stimulation, the circulating HIV population stores memories of host-pathogen combat won by the virus. We describe an exactly solvable model that captures the main qualitative features of the sets of sequences and a simple mechanistic model for the origin of the observed scaling laws. Our results define collective mutational pathways used by HIV to evade human immune responses, which could guide vaccine design.

Publisher's Note: Transient Casimir Forces from Quenches in Thermal and Active Matter [Phys. Rev. Lett. 118, 015702 (2017)].

This corrects the article DOI: 10.1103/PhysRevLett.118.015702.

Transient Casimir Forces from Quenches in Thermal and Active Matter.

We compute fluctuation-induced (Casimir) forces for classical systems after a temperature quench. Using a generic coarse-grained model for fluctuations of a conserved density, we find that transient forces arise even if the initial and final states are force free. In setups reminiscent of Casimir (planar walls) and van der Waals (small inclusions) interactions, we find comparable exact universal expressions for the force. Dynamical details only scale the time axis of transient force curves. We propose that such quenches can be achieved, for instance, in experiments on active matter, employing tunable activity or interaction protocols.

Active Particles with Soft and Curved Walls: Equation of State, Ratchets, and Instabilities.

We study, from first principles, the pressure exerted by an active fluid of spherical particles on general boundaries in two dimensions. We show that, despite the nonuniform pressure along curved walls, an equation of state is recovered upon a proper spatial averaging. This holds even in the presence of pairwise interactions between particles or when asymmetric walls induce ratchet currents, which are accompanied by spontaneous shear stresses on the walls. For flexible obstacles, the pressure inhomogeneities lead to a modulational instability as well as to the spontaneous motion of short semiflexible filaments. Finally, we relate the force exerted on objects immersed in active baths to the particle flux they generate around them.

Quorum sensing allows T cells to discriminate between self and nonself.

T cells orchestrate pathogen-specific adaptive immune responses by identifying peptides derived from pathogenic proteins that are displayed on the surface of infected cells. Host cells also display peptide fragments from the host's own proteins. Incorrectly identifying peptides derived from the body's own proteome as pathogenic can result in autoimmune disease. To minimize autoreactivity, immature T cells that respond to self-peptides are deleted in the thymus by a process called negative selection. However, negative selection is imperfect, and autoreactive T cells exist in healthy individuals. To understand how autoimmunity is yet avoided, without loss of responsiveness to pathogens, we have developed a model of T-cell training and response. Our model shows that T cells reliably respond to infection and avoid autoimmunity because collective decisions made by the T-cell population, rather than the responses of individual T cells, determine biological outcomes. The theory is qualitatively consistent with experimental data and yields a criterion for thymic selection to be adequate for suppressing autoimmunity.

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 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.

Coalescence Model for Crumpled Globules Formed in Polymer Collapse.

The rapid collapse of a polymer, due to external forces or changes in solvent, yields a long-lived "crumpled globule." The conjectured fractal structure shaped by hierarchical collapse dynamics has proved difficult to establish, even with large simulations. To unravel this puzzle, we study a coarse-grained model of in-falling spherical blobs that coalesce upon contact. Distances between pairs of monomers are assigned upon their initial coalescence, and do not "equilibrate" subsequently. Surprisingly, the model reproduces quantitatively the dependence of distance on segment length, suggesting that the slow approach to scaling is related to the wide distribution of blob sizes.